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1.
Cancer Genomics Proteomics ; 18(5): 661-673, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34479918

RESUMO

BACKGROUND/AIM: Coronavirus disease 2019 (COVID-19) poses a great challenge for the treatment of cancer patients. It presents as a severe respiratory infection in aged individuals, including some lung cancer patients. COVID-19 may be linked to the progression of aggressive lung cancer. In addition, the side effects of chemotherapy, such as chemotherapy resistance and the acceleration of cellular senescence, can worsen COVID-19. Given this situation, we investigated the role of paclitaxel (a chemotherapy drug) in the cell proliferation, apoptosis, and cellular senescence of gefitinib-resistant non-small-cell lung cancer (NSCLC) cells (PC9-MET) to clarify the underlying mechanisms. MATERIALS AND METHODS: PC9-MET cells were treated with paclitaxel for 72 h and then evaluated by a cell viability assay, DAPI staining, Giemsa staining, apoptosis assay, a reactive oxygen species (ROS) assay, SA-ß-Gal staining, a terminal deoxynucleotidyl transferase dUTP nick-end labeling assay and Western blotting. RESULTS: Paclitaxel significantly reduced the viability of PC9-MET cells and induced morphological signs of apoptosis. The apoptotic effects of paclitaxel were observed by increased levels of cleaved caspase-3 (Asp 175), cleaved caspase-9 (Asp 330) and cleaved PARP (Asp 214). In addition, paclitaxel increased ROS production, leading to DNA damage. Inhibition of ROS production by N-acetylcysteine attenuates paclitaxel-induced DNA damage. Importantly, paclitaxel eliminated cellular senescence, as observed by SA-ß-Gal staining. Cellular senescence elimination was associated with p53/p21 and p16/pRb signaling inactivation. CONCLUSION: Paclitaxel may be a promising anticancer drug and offer a new therapeutic strategy for managing gefitinib-resistant NSCLC during the COVID-19 pandemic.


Assuntos
Antineoplásicos/farmacologia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Gefitinibe/farmacologia , Neoplasias Pulmonares/tratamento farmacológico , Paclitaxel/farmacologia , Apoptose/efeitos dos fármacos , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Senescência Celular/efeitos dos fármacos , Humanos , Neoplasias Pulmonares/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos
2.
Int J Mol Sci ; 22(16)2021 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-34445495

RESUMO

As the most common gene mutation found in cancers, p53 mutations are detected in up to 96% of high-grade serous ovarian carcinoma (HGSOC). Meanwhile, mutant p53 overexpression is known to drive oncogenic phenotypes in cancer patients and to sustain the activation of EGFR signaling. Previously, we have demonstrated that the combined inhibition of EGFR and MDM2-p53 pathways, by gefitinib and JNJ-26854165, exerts a strong synergistic lethal effect on HGSOC cells. In this study, we investigated whether the gain-of-function p53 mutation (p53R248Q) overexpression could affect EGFR-related signaling and the corresponding drug inhibition outcome in HGSOC. The targeted inhibition responses of gefitinib and JNJ-26854165, in p53R248Q-overexpressing cells, were extensively evaluated. We found that the phosphorylation of AKT increased when p53R248Q was transiently overexpressed. Immunocytochemistry analysis further showed that upon p53R248Q overexpression, several AKT-related regulatory proteins translocated in unique intracellular patterns. Subsequent analysis revealed that, under the combined inhibition of gefitinib and JNJ-26854165, the cytonuclear trafficking of EGFR and MDM2 was disrupted. Next, we analyzed the gefitinib and JNJ-26854165 responses and found differential sensitivity to the single- or combined-drug inhibitions in p53R248Q-overexpressing cells. Our findings suggested that the R248Q mutation of p53 in HGSOC caused significant changes in signaling protein function and trafficking, under EGFR/MDM2-targeted inhibition. Such knowledge could help to advance our understanding of the role of mutant p53 in ovarian carcinoma and to improve the prognosis of patients receiving EGFR/MDM2-targeted therapies.


Assuntos
Carcinoma Epitelial do Ovário/genética , Cistadenocarcinoma Seroso/genética , Mutação com Ganho de Função , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteína Supressora de Tumor p53/genética , Regulação para Cima , Carcinoma Epitelial do Ovário/tratamento farmacológico , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cistadenocarcinoma Seroso/tratamento farmacológico , Receptores ErbB/antagonistas & inibidores , Feminino , Gefitinibe/farmacologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Fosforilação/efeitos dos fármacos , Transporte Proteico/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-mdm2/antagonistas & inibidores , Transdução de Sinais/efeitos dos fármacos , Triptaminas/farmacologia
3.
Cancer Sci ; 112(9): 3810-3821, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34145929

RESUMO

Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are effective in patients with non-small-cell lung cancer (NSCLC) harboring EGFR mutations. However, due to acquired resistance to EGFR-TKIs, even patients on third-generation osimertinib have a poor prognosis. Resistance mechanisms are still not fully understood. Here, we demonstrate that the increased expression of MUSASHI-2 (MSI2), an RNA-binding protein, is a novel mechanism for resistance to EGFR-TKIs. We found that after a long-term exposure to gefitinib, the first-generation EGFR-TKI lung cancer cells harboring the EGFR-TKI-sensitive mutations became resistant to both gefitinib and osimertinib. Although other mutations in EGFR were not found, expression levels of Nanog, a stemness core protein, and activities of aldehyde dehydrogenase (ALDH) were increased, suggesting that cancer stem-like properties were increased. Transcriptome analysis revealed that MSI2 was among the stemness-related genes highly upregulated in EGFR-TKI-resistant cells. Knockdown of MSI2 reduced cancer stem-like properties, including the expression levels of Nanog, a core stemness factor. We demonstrated that knockdown of MSI2 restored sensitivity to osimertinib or gefitinib in EGFR-TKI-resistant cells to levels similar to those of parental cells in vitro. An RNA immunoprecipitation (RIP) assay revealed that antibodies against MSI2 were bound to Nanog mRNA, suggesting that MSI2 increases Nanog expression by binding to Nanog mRNA. Moreover, overexpression of MSI2 or Nanog conferred resistance to osimertinib or gefitinib in parental cells. Finally, MSI2 knockdown greatly increased the sensitivity to osimertinib in vivo. Collectively, our findings provide proof of principle that targeting the MSI2-Nanog axis in combination with EGFR-TKIs would effectively prevent the emergence of acquired resistance.


Assuntos
Acrilamidas/farmacologia , Adenocarcinoma de Pulmão/metabolismo , Compostos de Anilina/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Gefitinibe/farmacologia , Neoplasias Pulmonares/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Proteínas de Ligação a RNA/metabolismo , Regulação para Cima , Células A549 , Acrilamidas/uso terapêutico , Adenocarcinoma de Pulmão/patologia , Compostos de Anilina/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/genética , Resistencia a Medicamentos Antineoplásicos/genética , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/genética , Gefitinibe/uso terapêutico , Perfilação da Expressão Gênica , Técnicas de Silenciamento de Genes , Humanos , Neoplasias Pulmonares/patologia , Mutação , Proteína Homeobox Nanog/metabolismo , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas de Ligação a RNA/genética , Transcriptoma , Transfecção
4.
Medicine (Baltimore) ; 100(25): e26450, 2021 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-34160440

RESUMO

RATIONALE: The guidelines recommended gefitinib as a first-line targeted treatment for stage IV non-small-cell lung cancer (NSCLC) patients with EGFR mutations. However, resistance to gefitinib ensues invariably and there is little evidence as for the effectiveness of subsequent salvage treatment for patients without T790m mutation. The case is to evaluate the efficacy of erlotinib, another EGFR-TKI, after failed first-line use of gefitinib. PATIENT CONCERNS: We described a 55-year-old man with good performance status (PS). DIAGNOSES: He was histopathologically diagnosed stage IV lung adenocarcinoma with EGFR mutations in November 2018. INTERVENTIONS: He was administrated with gefitinib daily (250 mg) for activating epidermal growth factor receptor (EGFR) mutations (exon 19 deletions,19del), and combined with platinum-based dual-drug chemotherapy. During the target treatments, the optimal efficacy evaluation was partial remission (PR) with a 12-month progression-free survival (PFS) time. Later, the intracranial progression of the patient rendered the treatment change to erlotinib. OUTCOMES: It is surprising that the tumor lesion in brain as well as lung relieved obviously. His progression-free survival (PFS)was nearly 11 months, and the overall survival (OS)was>36 months up to now. The adverse events were tolerable. LESSIONS: This case manifests that re-biopsy of advanced or recurrent NSCLC is beneficial to make a better therapeutic regimen, and erlotinib can be used as a salvage treatment after gefitinib failure.


Assuntos
Neoplasias Encefálicas/terapia , Carcinoma Pulmonar de Células não Pequenas/terapia , Cloridrato de Erlotinib/uso terapêutico , Neoplasias Pulmonares/terapia , Recidiva Local de Neoplasia/terapia , Terapia de Salvação/métodos , Biópsia , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/mortalidade , Neoplasias Encefálicas/secundário , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Carcinoma Pulmonar de Células não Pequenas/secundário , Quimiorradioterapia/métodos , Resistencia a Medicamentos Antineoplásicos , Substituição de Medicamentos , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/genética , Cloridrato de Erlotinib/farmacologia , Gefitinibe/farmacologia , Gefitinibe/uso terapêutico , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Mutação , Recidiva Local de Neoplasia/diagnóstico , Recidiva Local de Neoplasia/patologia , Intervalo Livre de Progressão , Radioterapia de Intensidade Modulada , Critérios de Avaliação de Resposta em Tumores Sólidos
5.
Commun Biol ; 4(1): 778, 2021 06 23.
Artigo em Inglês | MEDLINE | ID: mdl-34163000

RESUMO

Cancer stem cells (CSCs) are regarded as essential targets to overcome tumor progression and therapeutic resistance; however, practical targeting approaches are limited. Here, we identify testis-specific Y-like protein 5 (TSPYL5) as an upstream regulator of CSC-associated genes in non-small cell lung cancer cells, and suggest as a therapeutic target for CSC elimination. TSPYL5 elevation is driven by AKT-dependent TSPYL5 phosphorylation at threonine-120 and stabilization via inhibiting its ubiquitination. TSPYL5-pT120 also induces nuclear translocation and functions as a transcriptional activator of CSC-associated genes, ALDH1 and CD44. Also, nuclear TSPYL5 suppresses the transcription of PTEN, a negative regulator of PI3K signaling. TSPYL5-pT120 maintains persistent CSC-like characteristics via transcriptional activation of CSC-associated genes and a positive feedback loop consisting of AKT/TSPYL5/PTEN signaling pathway. Accordingly, elimination of TSPYL5 by inhibiting TSPYL5-pT120 can block aberrant AKT/TSPYL5/PTEN cyclic signaling and TSPYL5-mediated cancer stemness regulation. Our study suggests TSPYL5 be an effective target for therapy-resistant cancer.


Assuntos
Neoplasias Pulmonares/tratamento farmacológico , Células-Tronco Neoplásicas/efeitos dos fármacos , Proteínas Nucleares/antagonistas & inibidores , PTEN Fosfo-Hidrolase/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Transporte Ativo do Núcleo Celular , Animais , Linhagem Celular Tumoral , Transição Epitelial-Mesenquimal , Feminino , Gefitinibe/farmacologia , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Terapia de Alvo Molecular , Proteínas Nucleares/fisiologia , PTEN Fosfo-Hidrolase/fisiologia , Fosforilação , Proteínas Proto-Oncogênicas c-akt/fisiologia , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia
6.
Cell Death Dis ; 12(6): 561, 2021 05 31.
Artigo em Inglês | MEDLINE | ID: mdl-34059647

RESUMO

Lung cancer is one of the most aggressive cancers with poor prognosis and high resistance rate. The family of signal transducer and activator of transcriptions (STATs) appears to modulate resistance in non-small cell lung cancer (NSCLC). In this work, we demonstrated that STAT3/ZEB1 is a critical axis in gefitinib resistance. STAT3-targeted inhibition therefore is a new potential therapeutic strategy for gefitinib resistance in lung cancer. Our small molecule screening identified a relatively specific STAT3-targeted inhibitor, LL1. Pharmacological and biochemical studies indicated that LL1 block the activation of STAT3 via inhibiting its phosphorylation. Further in vitro and in vivo studies elucidated that LL1 sensitizes the resistance cells to gefitinib through depleting STAT3 activity and blocking STAT3/ZEB1 signaling pathways. Little toxicity of LL1 was observed in animal models. All these favorable results indicated that LL1 is a chemotherapeutic adjuvant for gefitinib resistance in NSCLC.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Gefitinibe/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Fator de Transcrição STAT3/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Desenvolvimento de Medicamentos , Gefitinibe/farmacologia , Humanos , Neoplasias Pulmonares/patologia , Inibidores de Proteínas Quinases/farmacologia , Transdução de Sinais
7.
J Thorac Oncol ; 16(9): 1533-1546, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34033974

RESUMO

INTRODUCTION: Blocking vascular endothelial growth factor pathway can enhance the efficacy of EGFR tyrosine kinase inhibitors in EGFR-mutant NSCLC. ACTIVE is the first phase 3 study conducted in the People's Republic of China evaluating apatinib, a vascular endothelial growth factor receptor 2 tyrosine kinase inhibitor, plus gefitinib as first-line therapy in EGFR-mutant NSCLC. METHODS: Treatment-naive patients with stage IIIB or IV nonsquamous NSCLC, an Eastern Cooperative Oncology Group performance status of 0 or 1, and EGFR exon 19 deletion or exon 21 L858R mutation were randomized 1:1 to receive oral gefitinib (250 mg/d), plus apatinib (500 mg/d; apatinib [A] + gefitinib [G] group), or placebo (placebo [P] + gefitinib [G] group). Stratification factors were mutation type, sex, and performance status. The primary end point was progression-free survival (PFS) by blinded independent radiology review committee (IRRC). Secondary end points were investigator-assessed PFS, overall survival, quality of life (QoL), safety, etc. Next-generation sequencing was used to explore efficacy predictors and acquired resistance. RESULTS: A total of 313 patients were assigned to the A + G (n = 157) or P + G group (n = 156). Median IRRC PFS in the A + G group was 13.7 months versus 10.2 months in the P + G group (hazard ratio 0.71, p = 0.0189). Investigator- and IRRC-assessed PFS were similar. Overall survival was immature. The most common treatment-emergent adverse events greater than or equal to grade 3 were hypertension (46.5%) and proteinuria (17.8%) in the A + G group and increased alanine aminotransferase (10.4%) and aspartate aminotransferase (3.2%) in the P + G group. QoL in the two groups had no statistical differences. Post hoc analysis revealed PFS benefits tended to favor the A + G group in patients with TP53 exon 8 mutation. CONCLUSIONS: Apatinib + gefitinib as first-line therapy had superior PFS in advanced EGFR-mutant NSCLC versus placebo + gefitinib. Combination therapy brought more adverse events but did not interfere QoL. TRIAL REGISTRATION: NCT02824458.


Assuntos
Neoplasias Pulmonares , Qualidade de Vida , Protocolos de Quimioterapia Combinada Antineoplásica , Intervalo Livre de Doença , Receptores ErbB/genética , Receptores ErbB/uso terapêutico , Gefitinibe/farmacologia , Gefitinibe/uso terapêutico , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Mutação , Inibidores de Proteínas Quinases/uso terapêutico , Piridinas , Quinazolinas/uso terapêutico , Fator A de Crescimento do Endotélio Vascular
8.
Mol Cell Biochem ; 476(10): 3563-3575, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34018148

RESUMO

Lung cancer is still a main cause of cancer-related death worldwide. Non-small-cell lung cancer (NSCLC) accounts for the majority of lung cancers, and gefitinib is an effective targeted drug for NSCLC. It is important to explore the underlying molecular mechanisms of gefitinib resistance to provide new treatment strategies and to improve the prognosis of gefitinib-resistant NSCLC patients. This study aimed to examine the role of filamin A (FLNA) in acquired resistance to gefitinib in NSCLC, and identify ANXA2 (annexin A2), one of calcium-dependent phospholipid-binding proteins, as its corresponding regulatory factor. First, we established resistant cells via long-term exposure to gefitinib to analyse the association between FLNA and gefitinib resistance. Through quantitative real-time polymerase chain reaction (qRT-PCR), Cell Counting Kit-8 (CCK-8), western blotting (WB), and flow cytometry assays, we evaluated the role of FLNA. The effect of FLNA knockdown or overexpression was analysed not only in cell lines but also in mouse models. We verified the FLNA-interacting protein through coimmunoprecipitation (CoIP) experiments and found that the downstream signalling pathway was regulated by FLNA and its interacting protein. Finally, the upstream transcription factor was identified by chromatin immunoprecipitation (ChIP). Increased FLNA expression induced gefitinib resistance. Knockdown of FLNA restored gefitinib sensitivity and induced apoptosis in vivo and in vitro. FLNA and ANXA2 cooperatively led to the activation of the Wnt pathway, which was closely linked to gefitinib resistance. Subsequently, SP1 promoted transcriptional activation of FLNA to regulate gefitinib resistance. We determined that FLNA serves as a regulator of gefitinib resistance in NSCLC and found that FLNA and ANXA2 together induced gefitinib resistance by activating the Wnt pathway.


Assuntos
Anexina A2/metabolismo , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Filaminas/metabolismo , Gefitinibe/farmacologia , Neoplasias Pulmonares/metabolismo , Proteínas de Neoplasias/metabolismo , Via de Sinalização Wnt/efeitos dos fármacos , Anexina A2/genética , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Filaminas/genética , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Proteínas de Neoplasias/genética
9.
Life Sci ; 277: 119608, 2021 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-33989664

RESUMO

AIMS: The first-generation epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI), gefitinib, continues to be a primary treatment option for lung cancer patients. However, acquisition of resistance to gefitinib is a major obstacle in lung cancer treatment and its cause is poorly understood. The present study aimed to implicate the role of SOX9-ß-catenin in developed resistance to gefitinib through epithelial to mesenchymal transition (EMT) in lung cancer in vitro and ex vivo. MAIN METHODS: Expression effect of SOX9 on survivability of lung cancer patients was demonstrated through online available Kaplan-Meier Plotter data base. Then, cell viability assay, colony forming assay, cell migration and invasion assays, flow cytometry, drug efflux assay, qRT-PCR, and western blotting were conducted to confirmed the role of SOX9 in gefitinib resistance in lung cancer cells. Dual-luciferase assay established the regulatory relation between SOX9 and ß-catenin. Multicellular spheroid assay further explored that down regulation of SOX9 could reverse gefitinib resistance ex vivo. KEY FINDINGS: Kaplan-Meier method correlated the higher expression of SOX9 and ß-catenin with poor overall survival of lung cancer patients. Upregulation of SOX9 was associated gefitinib resistance with increased cell proliferation, migration and invasion, single-cell colony-forming ability, reduced apoptosis, and gefitinib intake in lung cancer cells. Moreover, upregulated SOX9 promoted EMT via targeting ß-catenin and knockdown of SOX9 reversed the resistance and EMT phenotype. Similarly, we found that multicellular spheroid of gefitinib resistant cells showed larger surface area with more dispersion and viability of cells, while SOX9 knockdown abolished these induced properties ex vivo. SIGNIFICANCE: SOX9 expression could provide an innovative perspective as biomarker to understand the EGFR-TKIs resistance in lung cancer.


Assuntos
Neoplasias Pulmonares/metabolismo , Fatores de Transcrição SOX9/metabolismo , beta Catenina/metabolismo , Células A549 , Animais , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Transição Epitelial-Mesenquimal/genética , Transição Epitelial-Mesenquimal/fisiologia , Receptores ErbB/metabolismo , Gefitinibe/farmacologia , Humanos , Camundongos , Camundongos Nus , Inibidores de Proteínas Quinases/farmacologia , Proteínas Tirosina Quinases/antagonistas & inibidores , Proteínas Tirosina Quinases/metabolismo , Fatores de Transcrição SOX9/genética , Transdução de Sinais/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
10.
Nat Commun ; 12(1): 2581, 2021 05 10.
Artigo em Inglês | MEDLINE | ID: mdl-33972544

RESUMO

While the potential of patient-derived organoids (PDOs) to predict patients' responses to anti-cancer treatments has been well recognized, the lengthy time and the low efficiency in establishing PDOs hamper the implementation of PDO-based drug sensitivity tests in clinics. We first adapt a mechanical sample processing method to generate lung cancer organoids (LCOs) from surgically resected and biopsy tumor tissues. The LCOs recapitulate the histological and genetic features of the parental tumors and have the potential to expand indefinitely. By employing an integrated superhydrophobic microwell array chip (InSMAR-chip), we demonstrate hundreds of LCOs, a number that can be generated from most of the samples at passage 0, are sufficient to produce clinically meaningful drug responses within a week. The results prove our one-week drug tests are in good agreement with patient-derived xenografts, genetic mutations of tumors, and clinical outcomes. The LCO model coupled with the microwell device provides a technically feasible means for predicting patient-specific drug responses in clinical settings.


Assuntos
Adenocarcinoma/tratamento farmacológico , Antineoplásicos/farmacologia , Carcinoma de Células Escamosas/tratamento farmacológico , Técnicas de Cultura de Células/métodos , Ensaios de Seleção de Medicamentos Antitumorais/métodos , Neoplasias Pulmonares/tratamento farmacológico , Organoides/efeitos dos fármacos , Adenocarcinoma/genética , Adenocarcinoma/metabolismo , Adenocarcinoma/patologia , Animais , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patologia , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais/instrumentação , Gefitinibe/farmacologia , Humanos , Imuno-Histoquímica , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Masculino , Camundongos , Camundongos Endogâmicos NOD , Organoides/citologia , Organoides/patologia , Preparações Farmacêuticas , Ensaios Antitumorais Modelo de Xenoenxerto
11.
Cancer Sci ; 112(10): 4139-4150, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34058054

RESUMO

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) (eg, gefitinib) exert potent therapeutic efficacy in non-small-cell lung cancer (NSCLC) harboring EGFR-activating mutations. However, the resistance to EGFR TKIs limits their clinical therapeutic efficacy. TIP30, a newly identified tumor suppressor, appears to be involved in the regulation of cytoplasmic and nuclear EGFR signaling in NSCLC. Our previous study demonstrated that TIP30 regulated EGF-dependent cyclin D1 transcription in human lung adenocarcinoma and suppressed tumorigenesis. In the present study, the involvement of TIP30 in combating gefitinib resistance in NSCLC was determined for the first time in vitro and in vivo. Gain and loss of function studies showed that overexpression of TIP30 effectively sensitized cells to gefitinib in vitro, whereas TIP30 inhibition promoted gefitinib cell resistance. Moreover, TIP30 negatively regulated the activation of the p-AKT and p-MEK signaling pathways in PC9/GR. Importantly, PC9/GR harbored high levels of nuclear EGFR, and overexpression of TIP30 restored irregular EGFR trafficking and degradation from early endosomes to the late endosomes, decreasing the nuclear accumulation of EGFR, which may partly or totally inhibit EGFR-mediated induction of c-Myc transcription. Xenographic tumors induced by overexpression of TIP30 by PC9/GR cells in nude mice were suppressed compared with their original counterparts. Overall, it was revealed that TIP30 overexpression restored gefitinib sensitivity in NSCLC cells and attenuated the cytoplasmic and nuclear EGFR signaling pathways and may be a promising biomarker in gefitinib resistance in NSCLC.


Assuntos
Acetiltransferases/metabolismo , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Resistencia a Medicamentos Antineoplásicos/fisiologia , Neoplasias Pulmonares/metabolismo , Fatores de Transcrição/metabolismo , Animais , Antineoplásicos/farmacologia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Núcleo Celular/metabolismo , Ciclina D1/metabolismo , Citoplasma/metabolismo , Endossomos/metabolismo , Receptores ErbB/genética , Receptores ErbB/metabolismo , Gefitinibe/farmacologia , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Lisossomos/metabolismo , MAP Quinase Quinase 1/metabolismo , Camundongos , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Proto-Oncogênicas c-myc/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Regulação para Cima , Ensaios Antitumorais Modelo de Xenoenxerto
12.
Molecules ; 26(5)2021 Mar 09.
Artigo em Inglês | MEDLINE | ID: mdl-33803355

RESUMO

A series of 30 non-covalent imidazo[1,2-a]quinoxaline-based inhibitors of epidermal growth factor receptor (EGFR) were designed and synthesized. EGFR inhibitory assessment (against wild type) data of compounds revealed 6b, 7h, 7j, 9a and 9c as potent EGFRWT inhibitors with IC50 values of 211.22, 222.21, 193.18, 223.32 and 221.53 nM, respectively, which were comparable to erlotinib (221.03 nM), a positive control. Furthermore, compounds exhibited excellent antiproliferative activity when tested against cancer cell lines harboring EGFRWT; A549, a non-small cell lung cancer (NSCLC), HCT-116 (colon), MDA-MB-231 (breast) and gefitinib-resistant NSCLC cell line H1975 harboring EGFRL858R/T790M. In particular, compound 6b demonstrated significant inhibitory potential against gefitinib-resistant H1975 cells (IC50 = 3.65 µM) as compared to gefitinib (IC50 > 20 µM). Moreover, molecular docking disclosed the binding mode of the 6b to the domain of EGFR (wild type and mutant type), indicating the basis of inhibition. Furthermore, its effects on redox modulation, mitochondrial membrane potential, cell cycle analysis and cell death mode in A549 lung cancer cells were also reported.


Assuntos
Receptores ErbB/antagonistas & inibidores , Quinoxalinas/química , Quinoxalinas/farmacologia , Células A549 , Antineoplásicos/farmacologia , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Receptores ErbB/metabolismo , Cloridrato de Erlotinib/farmacologia , Gefitinibe/farmacologia , Humanos , Imidazóis/química , Imidazóis/farmacologia , Concentração Inibidora 50 , Neoplasias Pulmonares/metabolismo , Simulação de Acoplamento Molecular , Mutação/efeitos dos fármacos , Inibidores de Proteínas Quinases/farmacologia , Relação Estrutura-Atividade
13.
Int J Mol Sci ; 22(8)2021 Apr 11.
Artigo em Inglês | MEDLINE | ID: mdl-33920356

RESUMO

Adequate stress on the Endoplasmic Reticulum (ER) with the Unfolded Protein Response (UPR) could maintain glioma malignancy. Uncontrolled ER stress, on the other hand, predisposes an apoptosis-dominant UPR program. We studied here the proapoptotic actions of the Epidermal Growth Factor Receptor (EGFR) inhibitor gefitinib, with the focus on ER stress. The study models were human H4 and U87 glioma cell lines. We found that the glioma cell-killing effects of gefitinib involved caspase 3 apoptotic cascades. Three branches of ER stress, namely Activating Transcription Factor-6 (ATF6), Protein Kinase R (PKR)-Like ER Kinase (PERK), and Inositol-Requiring Enzyme 1 (IRE1), were activated by gefitinib, along with the elevation of intracellular free Ca2+, Reactive Oxygen Species (ROS), and NADPH Oxidase2/4 (NOX2/4). Specifically, elevated IRE1 phosphorylation, Tumor Necrosis Factor (TNF) Receptor-Associated Factor-2 (TRAF2) expression, Apoptosis Signal-Regulating Kinase-1 (Ask1) phosphorylation, c-Jun N-Terminal Kinase (JNK) phosphorylation, and Noxa expression appeared in gefitinib-treated glioma cells. Genetic, pharmacological, and biochemical studies further indicated an active ROS/ER stress/Ask1/JNK/Noxa axis causing the glioma apoptosis induced by gefitinib. The findings suggest that ER-stress-based therapeutic targeting could be a promising option in EGFR inhibitor glioma therapy, and may ultimately achieve a better patient response.


Assuntos
Apoptose/efeitos dos fármacos , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Gefitinibe/farmacologia , Glioma/tratamento farmacológico , Transdução de Sinais/efeitos dos fármacos , Linhagem Celular Tumoral , Glioma/metabolismo , Glioma/patologia , Humanos , Proteínas de Neoplasias/metabolismo
14.
Front Immunol ; 12: 648710, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33868285

RESUMO

The global rise of antibiotic-resistant strains of Salmonella has necessitated the development of alternative therapeutic strategies. Recent studies have shown that targeting host factors may provide an alternative approach for the treatment of intracellular pathogens. Host-directed therapy (HDT) modulates host cellular factors that are essential to support the replication of the intracellular pathogens. In the current study, we identified Gefitinib as a potential host directed therapeutic drug against Salmonella. Further, using the proteome analysis of Salmonella-infected macrophages, we identified EGFR, a host factor, promoting intracellular survival of Salmonella via mTOR-HIF-1α axis. Blocking of EGFR, mTOR or HIF-1α inhibits the intracellular survival of Salmonella within the macrophages and in mice. Global proteo-metabolomics profiling indicated the upregulation of host factors predominantly associated with ATP turn over, glycolysis, urea cycle, which ultimately promote the activation of EGFR-HIF1α signaling upon infection. Importantly, inhibition of EGFR and HIF1α restored both proteomics and metabolomics changes caused by Salmonella infection. Taken together, this study identifies Gefitinib as a host directed drug that holds potential translational values against Salmonella infection and might be useful for the treatment of other intracellular infections.


Assuntos
Gefitinibe/farmacologia , Metabolômica/métodos , Proteômica/métodos , Infecções por Salmonella/prevenção & controle , Salmonella/efeitos dos fármacos , Animais , Células Cultivadas , Receptores ErbB/imunologia , Receptores ErbB/metabolismo , Interações Hospedeiro-Patógeno/efeitos dos fármacos , Interações Hospedeiro-Patógeno/imunologia , Humanos , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Macrófagos/microbiologia , Camundongos Endogâmicos C57BL , Viabilidade Microbiana/efeitos dos fármacos , Viabilidade Microbiana/imunologia , Inibidores de Proteínas Quinases/farmacologia , Salmonella/imunologia , Salmonella/fisiologia , Infecções por Salmonella/imunologia , Infecções por Salmonella/microbiologia , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/imunologia , Células THP-1
15.
Oxid Med Cell Longev ; 2021: 6633867, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33763171

RESUMO

Background: Acquired resistance occurred in the majority of nonsmall cell lung cancer (NSCLC) patients receiving epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) therapy, and this may be related to the activation of the HIF-1 pathway. Therefore, we examined the influence of the hypoxia-inducible factor-1 (HIF-1) pathway inhibition on the sensitivity of HCC827 gefitinib-resistant (HCC827 GR) cells with MET amplification to gefitinib. Methods: We established HCC827 GR cell line with MET amplification and set four groups with different treatment. An MTT assay, a colony formation analysis, and a wound healing assay were performed to determine the sensitivity change of HCC827 GR cells after different treatments. HIF-1α, p-EGFR, and p-Met levels were detected with western blot. Correlations among HIF-1α, p-EGFR, and p-Met levels of HCC827 GR cells with different treatments were analyzed with Pearson's correlation analysis. Results: HIF-1 inhibitor YC-1 enhanced the sensitivity of HCC827 GR cells to gefitinib. p-Met level was correlated with HIF-1α level, while there was no correlation between p-Met level and p-EGFR level. Conclusion: HIF-1 inhibitor YC-1 is able to reverse the acquired resistance of HCC827 GR to gefitinib, and the regulation of the HIF-1 pathway on MET may be one of the mechanisms.


Assuntos
Resistencia a Medicamentos Antineoplásicos/genética , Gefitinibe/farmacologia , Amplificação de Genes , Fator 1 Induzível por Hipóxia/antagonistas & inibidores , Indazóis/farmacologia , Mutação/genética , Proteínas Proto-Oncogênicas c-met/genética , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Regulação para Baixo/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Receptores ErbB/genética , Humanos , Fator 1 Induzível por Hipóxia/metabolismo , Fosforilação/efeitos dos fármacos , Ensaio Tumoral de Célula-Tronco , Cicatrização/efeitos dos fármacos
16.
J Biol Regul Homeost Agents ; 35(2): 583-591, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33768996

RESUMO

In order to explore the mechanism of gefitinib-acquired resistance in lung cancer, a new biomarker has been developed for early clinical diagnosis and intervention; human NSCLC (Non-Small Cell Lung Cancer) cell lines H292 (denoted as H292S) and PC9 (denoted as PC9S) were used to establish gefitinib-resistant NSCLC cell lines H292 and PC9 models. CCK-8 (Cell Counting Kit-8) method was used to test the drug resistance of the cells. circRNAs (circular RNAs) that were differentially expressed before and after resistance were screened by RNA sequencing technology. The effects of circSETD3 overexpression and interference on the sensitivity of gefitinib was observed to analyze the nuclear localization of circSETD3 and verify the interaction between circSETD3-miR-520h-ABCG2. The results showed that the most significant change in differential expression of human NSCLC cell lines before and after drug resistance was hsa_circ_0000567, that is, circSETD3, which is mainly present in the cytoplasm. In H292S and PC9S, compared with the negative control group, the cell proliferation ability of the overexpression group was significantly increased, and the apoptosis ability was significantly decreased. In H292R and PC9R, compared with the negative control group, the proliferation ability of the interference group was significantly decreased, and the apoptosis ability was significantly increased. Overexpression of circSETD3 to H292S and PC9S, the expression of ABCG2 increased significantly. Also, the expression of ABCG2 decreased significantly after transfection with miR-520h mimics. H292R and PC9R interfered with circSETD3, the expression of ABCG2 decreased significantly. Moreover, the expression of ABCG2 increased significantly after transfection with miR-520h inhibitor. In conclusion, circSETD3 can be used as a novel biomarker for lung cancer. It relieves miR-520h degradation of the transporter ABCG2 by down-regulating the miR-520h expression, causing gefitinib to be pumped out of the cell.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , MicroRNAs , Biomarcadores , Carcinoma Pulmonar de Células não Pequenas/genética , Linhagem Celular Tumoral , Proliferação de Células , Resistencia a Medicamentos Antineoplásicos/genética , Gefitinibe/farmacologia , Humanos , Neoplasias Pulmonares/genética , MicroRNAs/genética
17.
Biochem Biophys Res Commun ; 551: 21-26, 2021 04 30.
Artigo em Inglês | MEDLINE | ID: mdl-33714755

RESUMO

Lung cancer is a major health challenge worldwide. Gefitinib, a tyrosine kinase inhibitor (TKI), is the common therapeutic drug used in advanced non-small-cell lung cancer (NSCLC). However, it is eventually bound to face the problem of acquired drug resistance. In this work, we investigated the role of lncRNA MITA1 in the acquisition of gefitinib resistance in NSCLC and uncovered the possible underlying molecular mechanism of the same. Experiments were carried out using the HCC827 and HCC827GR cells. These were transfected with pcDNA-MITA1 or si-MITA1 and treated with gefitinib. Subsequently, lncRNA MITA1 mediated effect on cell viability and apoptosis were studied using the MTT and flow cytometry assays. Furthermore, using qRT-PCR, Western blotting, and immunofluorescence assays, the regulatory association between lncRNA MITA1 and markers of autophagy (LC3, Beclin-1, and p62) were examined by estimating their cellular protein levels. Also, these results were verified in the presence of an autophagy inhibitor bafilomycin A1. We found that MITA1 was highly upregulated in the gefitinib-resistant NSCLC cells, indicating the regulatory role of MITA1 in gefitinib resistance. Mechanistically, upregulated MITA1 led to gefitinib resistance by suppressing apoptosis, increasing cell viability, and inducing autophagy. Furthermore, these results were true when tested in the presence of bafilomycin A1. Our results suggest that MITA1 by inducing autophagy could be a key regulator of gefitinib resistance in NSCLC.


Assuntos
Autofagia/efeitos dos fármacos , Autofagia/genética , Resistencia a Medicamentos Antineoplásicos/genética , Gefitinibe/farmacologia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , RNA Longo não Codificante/genética , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Pulmonares/tratamento farmacológico
18.
Cell Death Dis ; 12(2): 170, 2021 02 10.
Artigo em Inglês | MEDLINE | ID: mdl-33568630

RESUMO

Epidermal growth factor receptor (EGFR) is a key oncogene in lung adenocarcinoma (LUAD). Resistance to EGFR tyrosine kinase inhibitors is a major obstacle for EGFR-mutant LUAD patients. Our gene chip array, quantitative polymerase chain reaction validation, and shRNA-based high-content screening identified the Akt kinase lanthionine synthetase C-like protein 2 (LANCL2) as a pro-proliferative gene in the EGFR-mutant LUAD cell line PC9. Therefore, we investigated whether LANCL2 plays a role in promoting cell proliferation and drug resistance in EGFR-mutant LUAD. In silico clinical correlation analysis using the Cancer Genome Atlas Lung Adenocarcinoma dataset revealed a positive correlation between LANCL2 and EGFR expression and an inverse relationship between LANCL2 gain-of-function and survival in LUAD patients. The EGFR-mutant LUAD cell lines PC9 and HCC827 displayed higher LANCL2 expression than the non-EGFR-mutant cell line A549. In addition, LANCL2 was downregulated following gefitinib+pemetrexed combination therapy in PC9 cells. LANCL2 knockdown reduced proliferation and enhanced apoptosis in PC9, HCC827, and A549 cells in vitro and suppressed murine PC9 xenograft tumor growth in vivo. Notably, LANCL2 overexpression rescued these effects and promoted gefitinib + pemetrexed resistance in PC9 and HCC827 cells. Pathway analysis and co-immunoprecipitation followed by mass spectrometry of differentially-expressed genes in LANCL2 knockdown cells revealed enrichment of several cancer signaling pathways. In addition, Filamin A and glutathione S-transferase Mu 3 were identified as two novel protein interactors of LANCL2. In conclusion, LANCL2 promotes tumorigenic proliferation, suppresses apoptosis, and promotes gefitinib+pemetrexed resistance in EGFR-mutant LUAD cells. Based on the positive association between LANCL2, EGFR, and downstream Akt signaling, LANCL2 may be a promising new therapeutic target for EGFR-mutant LUAD.


Assuntos
Adenocarcinoma de Pulmão/enzimologia , Apoptose , Proliferação de Células , Neoplasias Pulmonares/enzimologia , Proteínas de Membrana/metabolismo , Mutação , Proteínas de Ligação a Fosfato/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Células A549 , Adenocarcinoma de Pulmão/tratamento farmacológico , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/patologia , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos , Receptores ErbB/genética , Filaminas/genética , Filaminas/metabolismo , Gefitinibe/farmacologia , Regulação Neoplásica da Expressão Gênica , Redes Reguladoras de Genes , Glutationa Transferase/genética , Glutationa Transferase/metabolismo , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Masculino , Proteínas de Membrana/genética , Camundongos Endogâmicos BALB C , Camundongos Nus , Pemetrexede/farmacologia , Proteínas de Ligação a Fosfato/genética , Transdução de Sinais , Ensaios Antitumorais Modelo de Xenoenxerto
19.
Bioorg Med Chem ; 34: 116039, 2021 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-33556869

RESUMO

Azalamellarin N, a synthetic lactam congener of the marine natural product lamellarin N, and its A-ring-modified analogues were synthesized and evaluated as potent and non-covalent inhibitors of the drug-resistant epidermal growth factor receptor T790M/L858R mutant. An in vitro tyrosine kinase assay indicated that the inhibitory activities of the synthetic azalamellarin analogues were higher than those of the corresponding lamellarins. The azalamellarin analogue bearing two 3-(dimethylamino)propoxy groups at C20- and C21-positions exhibited the highest activity and selectivity against the mutant kinase [IC50 (T790M/L858R) = 1.7 nM; IC50 (WT) = 4.6 nM]. The inhibitory activity was attributed to the hydrogen bonding interaction between the lactam NH group of the B-ring and carbonyl group of a methionine residue.


Assuntos
Receptores ErbB/antagonistas & inibidores , Receptores ErbB/genética , Compostos Heterocíclicos de 4 ou mais Anéis/síntese química , Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacologia , Afatinib/farmacologia , Linhagem Celular Tumoral , Gefitinibe/farmacologia , Humanos , Modelos Moleculares , Estrutura Molecular , Mutação , Conformação Proteica
20.
EBioMedicine ; 64: 103220, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33529999

RESUMO

BACKGROUND: Overexpression of epidermal growth factor receptor (EGFR), and downstream pathway activation appears to be a common oncogenic driver in the majority of head and neck squamous cell cancers (HNSCCs); yet targeting EGFR for the treatment of HNSCC has met with limited success. Apart from the anti-EGFR antibody cetuximab, no small molecule EGFR/tyrosine kinase inhibitors (TKIs) have progressed to routine clinical use. The aim of this study was to determine factors contributing to the lack of response to TKIs and identify alternative therapeutic vulnerabilities. METHODS: Genomic and transcriptomic sequencing, high-throughput compound screens, overexpression and siRNA knockdown, western blot, in vivo xenograft studies. FINDINGS: We derived three pairs of isogenic gefitinib (TKI)-sensitive and resistant patient-derived HNSCC cell lines. Genomic sequencing of gefitinib-resistant cell lines identified a lack of activating and resistance-associated EGFR mutations. Instead, transcriptomic sequencing showed upregulated EMT gene signature in the gefitinib-resistant cells with a corresponding increase in their migratory phenotype. Additionally, the resistant cell displayed reduced growth rate. Surprisingly, while gefitinib-resistant cells were independent of EGFR for survival, they nonetheless displayed activation of downstream ERK and AKT signalling. High-throughput screening (HTS) of druggable, small molecule libraries revealed that the gefitinib-resistant cells were particularly sensitive to inhibitors of genes involved in cell cycle and mitosis, such as Aurora kinase inhibitors (AKIs), cyclin-dependent kinase (CDK) inhibitors, and microtubule inhibitors. Notably our results showed that in the EGFR inhibited state, Aurora kinases are essential for cell survival. INTERPRETATION: Our study demonstrates that in the absence of activating EGFR mutations, HNSCCs may gain resistance to gefitinib through decreased cell proliferation, which makes them exceptionally vulnerable to cell-cycle inhibitors. FUNDING: Agency for Science, Technology, and Research (A*STAR), National Medical Research Council (NMRC), and the National Institutes of Health (NIH)/National Cancer Institute (NCI).


Assuntos
Aurora Quinases/antagonistas & inibidores , Aurora Quinases/metabolismo , Biomarcadores Tumorais , Resistencia a Medicamentos Antineoplásicos/genética , Ensaios de Seleção de Medicamentos Antitumorais , Gefitinibe/farmacologia , Mutação , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/genética , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Receptores ErbB/genética , Imunofluorescência , Humanos , Modelos Biológicos , Bibliotecas de Moléculas Pequenas , Carcinoma de Células Escamosas de Cabeça e Pescoço
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