RESUMO
Leptomeningeal carcinomatosis (LMC) occurs frequently in non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) mutations and is associated with acquired resistance to EGFR tyrosine kinase inhibitors (EGFR-TKIs). However, the mechanism by which LMC acquires resistance to osimertinib, a third-generation EGFR-TKI, is unclear. In this study, we elucidated the resistance mechanism and searched for a novel therapeutic strategy. We induced osimertinib resistance in a mouse model of LMC using an EGFR-mutant NSCLC cell line (PC9) via continuous oral osimertinib treatment and administration of established resistant cells and examined the resistance mechanism using next-generation sequencing. We detected the Kirsten rat sarcoma (KRAS)-G12V mutation in resistant cells, which retained the EGFR exon 19 deletion. Experiments involving KRAS knockdown in resistant cells and KRAS-G12V overexpression in parental cells revealed the involvement of KRAS-G12V in osimertinib resistance. Cotreatment with trametinib (a MEK inhibitor) and osimertinib resensitized the cells to osimertinib. Furthermore, in the mouse model of LMC with resistant cells, combined osimertinib and trametinib treatment successfully controlled LMC progression. These findings suggest a potential novel therapy against KRAS-G12V-harboring osimertinib-resistant LMC in EGFR-mutant NSCLC.
Assuntos
Acrilamidas/administração & dosagem , Compostos de Anilina/administração & dosagem , Antineoplásicos/administração & dosagem , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Códon/genética , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Neoplasias Pulmonares/tratamento farmacológico , Carcinomatose Meníngea/tratamento farmacológico , Mutação , Inibidores de Proteínas Quinases/administração & dosagem , Proteínas Proto-Oncogênicas p21(ras)/genética , Piridonas/administração & dosagem , Pirimidinonas/administração & dosagem , Animais , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/genética , Resistencia a Medicamentos Antineoplásicos/genética , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/genética , Receptores ErbB/metabolismo , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Masculino , Carcinomatose Meníngea/genética , Carcinomatose Meníngea/metabolismo , Camundongos , Camundongos SCID , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Piridonas/farmacologia , Pirimidinonas/farmacologia , Transfecção , Resultado do Tratamento , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
BACKGROUND: Osimertinib demonstrated promising efficacy for refractory leptomeningeal metastases (LM) in preclinical data and a clinical study at 160 mg, but there is limited data for the standard 80 mg dose. METHODS: T790M-positive patients with suspected LM after classical epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) failure were enroled. RESULTS: We investigated 13 patients (5 definitive and 8 possible LM cases). In two of the five definitive cases with T790M in and outside the central nervous system (CNS), osimertinib was effective for both lesions, with cerebrospinal fluid (CSF) clearance of cancer cells and sensitive/T790M mutations. In three definitive cases with extra-CNS T790M without CSF T790M, cancer cells and sensitive mutations in the CSF persisted after osimertinib initiation. The median progression-free survival of all 13 patients was 7.2 months. Osimertinib was generally well-tolerated despite poor performance status, but interstitial lung disease (grade 2) was confirmed in one patient. Based on 25 samples from 13 patients, the osimertinib CSF penetration rate was 2.5±0.3%. CONCLUSIONS: Osimertinib 80 mg is a useful therapeutic option for refractory LM after classical EGFR-TKI failure. It appears more effective in CSF T790M-positive cases.
Assuntos
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Meníngeas/tratamento farmacológico , Neoplasias Meníngeas/secundário , Piperazinas/administração & dosagem , Inibidores de Proteínas Quinases/administração & dosagem , Acrilamidas , Idoso , Compostos de Anilina , Carcinoma Pulmonar de Células não Pequenas/líquido cefalorraquidiano , Carcinoma Pulmonar de Células não Pequenas/genética , Receptores ErbB/líquido cefalorraquidiano , Receptores ErbB/genética , Humanos , Doenças Pulmonares Intersticiais/induzido quimicamente , Doenças Pulmonares Intersticiais/epidemiologia , Neoplasias Pulmonares/líquido cefalorraquidiano , Neoplasias Pulmonares/genética , Neoplasias Meníngeas/líquido cefalorraquidiano , Neoplasias Meníngeas/genética , Pessoa de Meia-Idade , Mutação , Projetos Piloto , Piperazinas/efeitos adversos , Piperazinas/líquido cefalorraquidiano , Intervalo Livre de Progressão , Estudos Prospectivos , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/líquido cefalorraquidiano , Resultado do TratamentoRESUMO
Crizotinib, a first-generation anaplastic lymphoma kinase (ALK) tyrosine-kinase inhibitor, is known to be effective against echinoderm microtubule-associated protein-like 4 (EML4)-ALK-positive non-small cell lung cancers. Nonetheless, the tumors subsequently become resistant to crizotinib and recur in almost every case. The mechanism of the acquired resistance needs to be deciphered. In this study, we established crizotinib-resistant cells (A925LPE3-CR) via long-term administration of crizotinib to a mouse model of pleural carcinomatous effusions; this model involved implantation of the A925LPE3 cell line, which harbors the EML4-ALK gene rearrangement. The resistant cells did not have the secondary ALK mutations frequently occurring in crizotinib-resistant cells, and these cells were cross-resistant to alectinib and ceritinib as well. In cell clone #2, which is one of the clones of A925LPE3-CR, crizotinib sensitivity was restored via the inhibition of epidermal growth factor receptor (EGFR) by means of an EGFR tyrosine-kinase inhibitor (erlotinib) or an anti-EGFR antibody (cetuximab) in vitro and in the murine xenograft model. Cell clone #2 did not have an EGFR mutation, but the expression of amphiregulin (AREG), one of EGFR ligands, was significantly increased. A knockdown of AREG with small interfering RNAs restored the sensitivity to crizotinib. These data suggest that overexpression of EGFR ligands such as AREG can cause resistance to crizotinib, and that inhibition of EGFR signaling may be a promising strategy to overcome crizotinib resistance in EML4-ALK lung cancer.
Assuntos
Anfirregulina/metabolismo , Proteínas de Ciclo Celular/metabolismo , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/metabolismo , Neoplasias Pulmonares/metabolismo , Proteínas Associadas aos Microtúbulos/metabolismo , Pirazóis/farmacologia , Piridinas/farmacologia , Receptores Proteína Tirosina Quinases/metabolismo , Serina Endopeptidases/metabolismo , Anfirregulina/deficiência , Anfirregulina/genética , Quinase do Linfoma Anaplásico , Animais , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Crizotinibe , Modelos Animais de Doenças , Resistencia a Medicamentos Antineoplásicos/genética , Receptores ErbB/genética , Cloridrato de Erlotinib , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Masculino , Camundongos , Mutação , Derrame Pleural , Neoplasias Pleurais , Inibidores de Proteínas Quinases/farmacologia , RNA Interferente Pequeno/genética , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Small-cell lung cancer (SCLC) accounts for nearly 15% of lung cancer cases and exhibits aggressive clinical behavior characterized by rapid growth and metastatic spread to multiple organs. About 70% of patients with SCLC present with extensive disease and distant metastases at diagnosis. HSP90 is a 90-kDa molecular chaperone whose association is required for the stability and function of its numerous "client proteins." Here, we assessed the therapeutic potential of the HSP90 inhibitor 17-DMAG in SCLC. Notably, 17-DMAG hindered the viability of human SCLC cell lines-regardless of their chemosensitivity-via the decreased expression of client proteins, including the proto-oncogene c-Raf (also known as RAF1). In an in vivo imaging model of SCLC multiple-organ metastasis with the human SCLC cell line SBC-5, treatment with 17-DMAG remarkably inhibited the formation of metastatic sites in the liver, but was ineffective in hindering the progression of bone lesions. The latter was likely the result of activation of osteoclasts. IGF-1, which is supposed to be rich in bone environment, preserved c-Raf expression and maintained viability of SBC-5 cells treated with 17-DMAG. Furthermore, the combined use of a bisphosphonate with 17-DMAG significantly attenuated the progression of metastases in both the liver and the bone. These findings suggest that therapeutic effects of HSP90 inhibitors may be organ-specific and should be carefully monitored in SCLC clinical trials.
Assuntos
Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Neoplasias Pulmonares/tratamento farmacológico , Carcinoma de Pequenas Células do Pulmão/tratamento farmacológico , Animais , Benzoquinonas/farmacologia , Neoplasias Ósseas/secundário , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Difosfonatos/administração & dosagem , Humanos , Imidazóis/administração & dosagem , Lactamas Macrocíclicas/farmacologia , Neoplasias Hepáticas/secundário , Neoplasias Pulmonares/patologia , Masculino , Camundongos , Especificidade de Órgãos , Proto-Oncogene Mas , Proteínas Proto-Oncogênicas c-raf/análise , Carcinoma de Pequenas Células do Pulmão/patologia , Ácido ZoledrônicoRESUMO
EML4-ALK lung cancer accounts for approximately 3-7% of non-small-cell lung cancer cases. To investigate the molecular mechanism underlying tumor progression and targeted drug sensitivity/resistance in EML4-ALK lung cancer, clinically relevant animal models are indispensable. In this study, we found that the lung adenocarcinoma cell line A925L expresses an EML4-ALK gene fusion (variant 5a, E2:A20) and is sensitive to the ALK inhibitors crizotinib and alectinib. We further established highly tumorigenic A925LPE3 cells, which also have the EML4-ALK gene fusion (variant 5a) and are sensitive to ALK inhibitors. By using A925LPE3 cells with luciferase gene transfection, we established in vivo imaging models for pleural carcinomatosis, bone metastasis, and brain metastasis, all of which are significant clinical concerns of advanced EML4-ALK lung cancer. Interestingly, crizotinib caused tumors to shrink in the pleural carcinomatosis model, but not in bone and brain metastasis models, whereas alectinib showed remarkable efficacy in all three models, indicative of the clinical efficacy of these ALK inhibitors. Our in vivo imaging models of multiple organ sites may provide useful resources to analyze further the pathogenesis of EML4-ALK lung cancer and its response and resistance to ALK inhibitors in various organ microenvironments.
Assuntos
Neoplasias Ósseas/diagnóstico por imagem , Neoplasias Encefálicas/diagnóstico por imagem , Carcinoma Pulmonar de Células não Pequenas/genética , Proteínas de Ciclo Celular/genética , Proteínas Associadas aos Microtúbulos/genética , Neoplasias Pleurais/diagnóstico por imagem , Receptores Proteína Tirosina Quinases/genética , Serina Endopeptidases/genética , Quinase do Linfoma Anaplásico , Animais , Antineoplásicos/farmacologia , Neoplasias Ósseas/tratamento farmacológico , Neoplasias Ósseas/secundário , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/secundário , Carbazóis/farmacologia , Linhagem Celular Tumoral , Crizotinibe , Feminino , Humanos , Neoplasias Pulmonares/genética , Masculino , Camundongos , Camundongos SCID , Proteínas de Fusão Oncogênica/genética , Piperidinas/farmacologia , Neoplasias Pleurais/tratamento farmacológico , Neoplasias Pleurais/secundário , Inibidores de Proteínas Quinases/farmacologia , Pirazóis/farmacologia , Piridinas/farmacologia , Radiografia , Receptores Proteína Tirosina Quinases/antagonistas & inibidoresRESUMO
We present the case of a 34-year-old Japanese man with anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer and brain metastases. After central nervous system (CNS) disease progression with alecintib and brigatinib, treatment with lorlatinib resulted in a good intracranial response. In this case, we investigated brain penetration ratio of brigatinib using cerebrospinal fluid and paired serum samples, and the ratio was 0.012. Further, we investigated resistance mechanisms via next-generation sequencing (NGS) using lung biopsy at lung cancer diagnosis and brain biopsy sample at progressive disease of brigatinib. No apparent resistance mechanism of known ALK resistance, such as ALK mutations, amplifications, epithelial-mesenchymal transition (EMT) and bypass pathway activation were detected. Taken together, we speculate that the low CNS penetration rate of brigatinib confers CNS progression. Further studies are warranted to reveal the resistance mechanism and propose a treatment strategy for CNS progression in ALK-positive patients.
Assuntos
Adenocarcinoma de Pulmão , Aminopiridinas , Quinase do Linfoma Anaplásico , Carbazóis , Resistencia a Medicamentos Antineoplásicos , Lactamas Macrocíclicas , Lactamas , Neoplasias Pulmonares , Compostos Organofosforados , Piperidinas , Pirazóis , Pirimidinas , Humanos , Masculino , Compostos Organofosforados/uso terapêutico , Compostos Organofosforados/farmacologia , Compostos Organofosforados/administração & dosagem , Lactamas/uso terapêutico , Adulto , Aminopiridinas/uso terapêutico , Aminopiridinas/farmacologia , Quinase do Linfoma Anaplásico/genética , Pirimidinas/uso terapêutico , Pirimidinas/farmacologia , Pirimidinas/administração & dosagem , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Lactamas Macrocíclicas/uso terapêutico , Lactamas Macrocíclicas/farmacologia , Adenocarcinoma de Pulmão/tratamento farmacológico , Adenocarcinoma de Pulmão/patologia , Adenocarcinoma de Pulmão/genética , Pirazóis/uso terapêutico , Pirazóis/farmacologia , Carbazóis/uso terapêutico , Carbazóis/farmacologia , Carbazóis/administração & dosagem , Piperidinas/uso terapêutico , Piperidinas/farmacologia , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/secundárioRESUMO
We report a case of limited effectiveness of dabrafenib and trametinib in a 59-year-old man with poorly differentiated lung carcinoma and a rare BRAF K601E mutation. The patient, unresponsive to chemotherapy and immunotherapy, received these targeted agents as second-line treatment. Despite a notable initial response, tumor regression lasted only 52 days. A subsequent liquid biopsy revealed additional alterations (BRAF amplification, KIT amplification, TP53 S241F), indicating a complex resistance mechanism. This case underscores the challenges in treating BRAF K601E-mutant lung carcinoma, emphasizing the need for advanced molecular diagnostics, personalized approaches, and further research into more effective therapies for unique genetic profiles.
RESUMO
The clinical development of Kirsten rat sarcoma virus (KRAS)-G12C inhibitors for the treatment of KRAS-mutant lung cancer is limited by the presence of co-mutations, intrinsic resistance, and the emergence of acquired resistance. Therefore, innovative strategies for enhancing apoptosis in KRAS-mutated non-small cell lung cancer (NSCLC) are urgently needed. Through CRISPR-Cas9 knockout screening using a library of 746 crRNAs and drug screening with a custom library of 432 compounds, we discover that WEE1 kinase inhibitors are potent enhancers of apoptosis, particularly in KRAS-mutant NSCLC cells harboring TP53 mutations. Mechanistically, WEE1 inhibition promotes G2/M transition and reduces checkpoint kinase 2 (CHK2) and Rad51 expression in the DNA damage response (DDR) pathway, which is associated with apoptosis and the repair of DNA double-strand breaks, leading to mitotic catastrophe. Notably, the combined inhibition of KRAS-G12C and WEE1 consistently suppresses tumor growth. Our results suggest targeting WEE1 as a promising therapeutic strategy for KRAS-mutated NSCLC with TP53 mutations.
Assuntos
Apoptose , Carcinoma Pulmonar de Células não Pequenas , Proteínas de Ciclo Celular , Neoplasias Pulmonares , Mutação , Proteínas Tirosina Quinases , Proteínas Proto-Oncogênicas p21(ras) , Proteína Supressora de Tumor p53 , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/patologia , Humanos , Proteínas Tirosina Quinases/genética , Proteínas Tirosina Quinases/antagonistas & inibidores , Proteínas Tirosina Quinases/metabolismo , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo , Proteínas Proto-Oncogênicas p21(ras)/genética , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Proteínas Proto-Oncogênicas p21(ras)/antagonistas & inibidores , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/antagonistas & inibidores , Proteínas de Ciclo Celular/metabolismo , Mutação/genética , Linhagem Celular Tumoral , Animais , Apoptose/efeitos dos fármacos , Apoptose/genética , Camundongos , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Camundongos Nus , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
There are limited methods to stably analyze the interactions between cancer cells and glial cells in vitro, which hinders our molecular understanding. Here, we develop a simple and stable culture method of mouse glial cells, termed mixed-glial culture on/in soft substrate (MGS), which serves well as a platform to study cancer-glia interactions. Using this method, we find that human lung cancer cells become overly dependent on metabotropic glutamate receptor 1 (mGluR1) signaling in the brain microenvironment. Mechanistically, interactions with astrocytes induce mGluR1 in cancer cells through the Wnt-5a/prickle planar cell polarity protein 1 (PRICKLE1)/RE1 silencing transcription factor (REST) axis. Induced mGluR1 directly interacts with and stabilizes the epidermal growth factor receptor (EGFR) in a glutamate-dependent manner, and these cells then become responsive to mGluR1 inhibition. Our results highlight increased dependence on mGluR1 signaling as an adaptive strategy and vulnerability of human lung cancer brain metastasis.
Assuntos
Neoplasias Encefálicas , Neoplasias Pulmonares , Receptores de Glutamato Metabotrópico , Camundongos , Animais , Humanos , Ácido Glutâmico , Astrócitos/metabolismo , Receptores de Glutamato Metabotrópico/metabolismo , Receptores ErbB , Microambiente TumoralRESUMO
Cerebrospinal fluid tumor-derived DNA (CSF-tDNA) analysis is a promising approach for monitoring the neoplastic processes of the central nervous system. We applied a lung cancer-specific sequencing panel (CAPP-Seq) to 81 CSF, blood, and tissue samples from 24 lung cancer patients who underwent lumbar puncture (LP) for suspected leptomeningeal disease (LMD). A subset of the cohort (N = 12) participated in a prospective trial of osimertinib for refractory LMD in which serial LPs were performed before and during treatment. CSF-tDNA variant allele fractions (VAFs) were significantly higher than plasma circulating tumor DNA (ctDNA) VAFs (median CSF-tDNA, 32.7%; median plasma ctDNA, 1.8%; P < 0.0001). Concentrations of tumor DNA in CSF and plasma were positively correlated (Spearman's ρ, 0.45; P = 0.03). For LMD diagnosis, cytology was 81.8% sensitive and CSF-tDNA was 91.7% sensitive. CSF-tDNA was also strongly prognostic for overall survival (HR = 7.1; P = 0.02). Among patients with progression on targeted therapy, resistance mutations, such as EGFR T790M and MET amplification, were common in peripheral blood but were rare in time-matched CSF, indicating differences in resistance mechanisms based on the anatomic compartment. In the osimertinib cohort, patients with CNS progression had increased CSF-tDNA VAFs at follow-up LP. Post-osimertinib CSF-tDNA VAF was strongly prognostic for CNS progression (HR = 6.2, P = 0.009). Detection of CSF-tDNA in lung cancer patients with suspected LMD is feasible and may have clinical utility. CSF-tDNA improves the sensitivity of LMD diagnosis, enables improved prognostication, and drives therapeutic strategies that account for spatial heterogeneity in resistance mechanisms.
RESUMO
Targeted therapy is effective in many tumor types including lung cancer, the leading cause of cancer mortality. Paradigm defining examples are targeted therapies directed against non-small cell lung cancer (NSCLC) subtypes with oncogenic alterations in EGFR, ALK and KRAS. The success of targeted therapy is limited by drug-tolerant persister cells (DTPs) which withstand and adapt to treatment and comprise the residual disease state that is typical during treatment with clinical targeted therapies. Here, we integrate studies in patient-derived and immunocompetent lung cancer models and clinical specimens obtained from patients on targeted therapy to uncover a focal adhesion kinase (FAK)-YAP signaling axis that promotes residual disease during oncogenic EGFR-, ALK-, and KRAS-targeted therapies. FAK-YAP signaling inhibition combined with the primary targeted therapy suppressed residual drug-tolerant cells and enhanced tumor responses. This study unveils a FAK-YAP signaling module that promotes residual disease in lung cancer and mechanism-based therapeutic strategies to improve tumor response.
Assuntos
Carcinoma Pulmonar de Células não Pequenas , Resistencia a Medicamentos Antineoplásicos , Neoplasias Pulmonares , Transdução de Sinais , Fatores de Transcrição , Proteínas de Sinalização YAP , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Transdução de Sinais/efeitos dos fármacos , Fatores de Transcrição/metabolismo , Fatores de Transcrição/genética , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Proteínas de Sinalização YAP/metabolismo , Linhagem Celular Tumoral , Animais , Resistencia a Medicamentos Antineoplásicos/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Neoplasia Residual , Camundongos , Quinase 1 de Adesão Focal/metabolismo , Quinase 1 de Adesão Focal/genética , Receptores ErbB/metabolismo , Receptores ErbB/genética , Quinase do Linfoma Anaplásico/metabolismo , Quinase do Linfoma Anaplásico/genética , Quinase do Linfoma Anaplásico/antagonistas & inibidores , Proteínas Proto-Oncogênicas p21(ras)/genética , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Proteína-Tirosina Quinases de Adesão Focal/metabolismo , Antineoplásicos/uso terapêutico , Antineoplásicos/farmacologia , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
In this study, the impact of the apolipoprotein B mRNA-editing catalytic subunit-like (APOBEC) enzyme APOBEC3B (A3B) on epidermal growth factor receptor (EGFR)-driven lung cancer was assessed. A3B expression in EGFR mutant (EGFRmut) non-small-cell lung cancer (NSCLC) mouse models constrained tumorigenesis, while A3B expression in tumors treated with EGFR-targeted cancer therapy was associated with treatment resistance. Analyses of human NSCLC models treated with EGFR-targeted therapy showed upregulation of A3B and revealed therapy-induced activation of nuclear factor kappa B (NF-κB) as an inducer of A3B expression. Significantly reduced viability was observed with A3B deficiency, and A3B was required for the enrichment of APOBEC mutation signatures, in targeted therapy-treated human NSCLC preclinical models. Upregulation of A3B was confirmed in patients with NSCLC treated with EGFR-targeted therapy. This study uncovers the multifaceted roles of A3B in NSCLC and identifies A3B as a potential target for more durable responses to targeted cancer therapy.
Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Animais , Camundongos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Mutação , Regulação para Cima/genética , Receptores ErbB/genética , Receptores ErbB/metabolismo , Citidina Desaminase/genética , Antígenos de Histocompatibilidade Menor/genética , Antígenos de Histocompatibilidade Menor/metabolismoRESUMO
Acquired resistance to epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs), such as gefitinib and erlotinib, is a critical problem in the management of patients with EGFR mutant lung cancer. Several mechanisms have been reported involved in this acquired resistance, including hepatocyte growth factor (HGF) activation of an alternative pathway. PI3K and mTOR are downstream molecules of receptor tyrosine kinases, such as EGFR and Met, and are thought to be ideal targets for controlling various tumor types. We assessed whether BEZ235, a dual inhibitor of PI3K and mTOR, could overcome the EGFR-TKI resistance induced by HGF in an EGFR mutant lung cancer model. Exogenous and endogenous HGF triggered resistance to erlotinib in the PC-9 and HCC827, EGFR mutant lung cancer cell lines. BEZ235 alone inhibited the viability of PC-9 and HCC827 cells in vitro, irrespective of the presence or the absence of HGF. Using a xenograft model of severe combined immunodeficient mice with HGF-gene-transfected PC-9 cells (PC-9/HGF), we found that BEZ235 inhibited tumor growth, whereas erlotinib did not. BEZ235 monotherapy also inhibited the phosphorylation of Akt and p70S6K/S6RP, downstream molecules of PI3K and mTOR, respectively, as well as suppressing tumor-cell proliferation and angiogenesis of PC-9/HGF tumors. These results suggest that BEZ235, even as monotherapy, may be useful in managing HGF-induced EGFR-TKI resistance in EGFR mutant lung cancer.
Assuntos
Antineoplásicos/farmacologia , Resistencia a Medicamentos Antineoplásicos , Imidazóis/farmacologia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/enzimologia , Quinazolinas/farmacologia , Quinolinas/farmacologia , Animais , Sobrevivência Celular , Receptores ErbB/metabolismo , Cloridrato de Erlotinib , Feminino , Humanos , Camundongos , Camundongos SCID , Mutação , Transplante de Neoplasias , Inibidores de Fosfoinositídeo-3 Quinase , Inibidores de Proteínas Quinases/farmacologia , Serina-Treonina Quinases TOR/antagonistas & inibidores , Sais de Tetrazólio/farmacologia , Tiazóis/farmacologia , Resultado do TratamentoRESUMO
BACKGROUND: The secondary epidermal growth factor receptor (EGFR) mutation Thr790Met (T790M) accounts for approximately half of acquired resistances to EGFR-tyrosine kinase inhibitor (TKI). Recent reports have demonstrated that the emergence of T790M predicts a favorable prognosis and indolent progression. However, rebiopsy to confirm T790M status can be challenging due to limited tissue availability and procedural feasibility, and little is known regarding the differences among patients with or without T790M mutation. METHODS: The study investigated 78 EGFR-mutant patients who had undergone rebiopsy after TKI failure. The peptide nucleic acid-locked nucleic acid polymerase chain reaction clamp method was used in EGFR mutational analyses. Various patient characteristics and postprogression survivals (PPSs) after initial TKI failure were retrospectively compared in patients with and without T790M. RESULTS: The T790M mutation was identified in 4 (17%) of 24 central nervous system lesions, and in 22 (41%) of 54 other lesions (P = .0417). No other characteristics had a statistical association with T790M prevalence. Median PPS was 31.4 months in 26 patients with T790M, and 11.4 months in 52 patients without T790M (P = .0017). In the multivariate analysis, statistically significant factors for longer PPS included T790M-positive, good performance status, and no carcinomatous meningitis. CONCLUSIONS: The emergence of T790M in central nervous system lesions was rare, compared with other lesions. Patients with T790M after TKI failure appear to have better prognoses than those without T790M. TKI rechallenge or continuous administration beyond progression may be effective after initial TKI failure.
Assuntos
Carcinoma Pulmonar de Células não Pequenas/patologia , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/genética , Neoplasias Pulmonares/patologia , Mutação , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Tirosina Quinases/antagonistas & inibidores , Idoso , Antineoplásicos/uso terapêutico , Biópsia/métodos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/enzimologia , Carcinoma Pulmonar de Células não Pequenas/genética , Análise Mutacional de DNA/métodos , Progressão da Doença , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/enzimologia , Neoplasias Pulmonares/genética , Masculino , Estudos RetrospectivosRESUMO
CONTEXT: Pancreatic cancer is frequently complicated by malignancies in other organs. However, synchronous triple cancers including pancreatic cancer have been seldom reported in the English language literature. CASE REPORT: We describe the rare case of a 77-year-old man with triple cancers of the pancreas, stomach, and cecum. Biopsies revealed that all three tumors were adenocarcinomas. The pancreatic and gastric tumors were positive for cytokeratin 7 and negative for cytokeratin 20, whereas the cecal tumor was negative for cytokeratin 7 and positive for cytokeratin 20. K-ras mutations were present at codon 12 in the pancreatic tumor and at codon 13 in the cecal tumor, but were absent from the gastric tumor. Since the three tumors had different characteristics, the patient was diagnosed with synchronous triple cancers. Because invasive surgery was required to remove all three tumors and the patient had risk factors for surgery, we elected to treat him with chemotherapy. All three cancers were markedly reduced in size by treatment with cycles of 100 mg/day S-1 for 2 weeks, followed by a 1-week rest. The patient later developed hypoproteinemia and anasarca, which was diagnosed as pancreatic exocrine insufficiency due to pancreatic head cancer. Treatment with pancrelipase resulted in dramatic improvements in hypoproteinemia and anasarca. CONCLUSIONS: This is the first case report in which S-1 was effective in triple cancers of the pancreas, stomach, and cecum. Patients with pancreatic head cancer should be monitored for pancreatic exocrine insufficiency.
Assuntos
Neoplasias do Ceco/tratamento farmacológico , Neoplasias Primárias Múltiplas/tratamento farmacológico , Ácido Oxônico/uso terapêutico , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Gástricas/tratamento farmacológico , Tegafur/uso terapêutico , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/genética , Adenocarcinoma/metabolismo , Idoso , Antineoplásicos/efeitos adversos , Antineoplásicos/uso terapêutico , Neoplasias do Ceco/genética , Neoplasias do Ceco/metabolismo , Combinação de Medicamentos , Edema/induzido quimicamente , Edema/tratamento farmacológico , Humanos , Hipoproteinemia/induzido quimicamente , Hipoproteinemia/tratamento farmacológico , Queratina-20/análise , Queratina-7/análise , Masculino , Mutação , Neoplasias Primárias Múltiplas/genética , Neoplasias Primárias Múltiplas/metabolismo , Ácido Oxônico/efeitos adversos , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/metabolismo , Pancrelipase/uso terapêutico , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas p21(ras) , Neoplasias Gástricas/genética , Neoplasias Gástricas/metabolismo , Tegafur/efeitos adversos , Resultado do Tratamento , Proteínas ras/genéticaRESUMO
BACKGROUND: Relatively little is known about acute exacerbation (AE) of interstitial pneumonia associated with collagen vascular diseases (CVD-IPs). OBJECTIVES: This study was aimed at clarifying clinical characteristics and outcome in AE of CVD-IPs, compared with those of idiopathic interstitial pneumonias (IIPs). METHODS: We retrospectively reviewed 112 admission cases with suspected AE of CVD-IPs or IIPs during 2003-2009. IIPs were diagnosed with idiopathic pulmonary fibrosis (IPF) or non-IPF, mostly based on radiologic findings. Of these, 15 AEs of CVD-IPs (6 rheumatoid arthritis, 6 dermatomyositis and 3 systemic sclerosis) and 47 AEs of IIPs (13 IPF and 34 non-IPF) were included. RESULTS: The clinical characteristics in AE of CVD-IPs were similar to those of IIPs, except for younger age (63.3 ± 6.8 vs. 73.8 ± 9.1 years; p = 0.0001) and higher PaO(2)/FiO(2) at the onset of AE (205 ± 81.2 vs. 145 ± 53.8 mm Hg; p = 0.002) in the former. Dermatomyositis-related interstitial pneumonia (IP) showed a relatively indolent onset and was often associated with worsening control of the underlying disease, whereas AE of other CVD-IPs resembled that of IIPs. 90-day mortality of 33% in AE of CVD-IPs was similar to that of IIPs (44%; p = 0.44) or non-IPF (34%; p = 0.94), but was significantly better than that of IPF (69%; p = 0.04). CONCLUSION: Clinical features and outcome in AE of CVD-IPs were similar, if not identical, to those of IIPs, having a significant impact on the clinical course. AE of advanced IPF with typical radiologic features seems to have higher mortality compared with other forms of IP.
Assuntos
Doenças do Colágeno/complicações , Fibrose Pulmonar Idiopática/complicações , Doenças Pulmonares Intersticiais/etiologia , Doenças Vasculares/complicações , Doença Aguda , Idoso , Biópsia , Lavagem Broncoalveolar , Doenças do Colágeno/diagnóstico , Doenças do Colágeno/mortalidade , Progressão da Doença , Feminino , Seguimentos , Humanos , Fibrose Pulmonar Idiopática/diagnóstico , Fibrose Pulmonar Idiopática/mortalidade , Japão/epidemiologia , Pulmão/diagnóstico por imagem , Pulmão/patologia , Doenças Pulmonares Intersticiais/diagnóstico , Doenças Pulmonares Intersticiais/mortalidade , Masculino , Pessoa de Meia-Idade , Radiografia Torácica , Recidiva , Estudos Retrospectivos , Fatores de Risco , Taxa de Sobrevida/tendências , Tomografia Computadorizada por Raios X , Doenças Vasculares/diagnóstico , Doenças Vasculares/mortalidadeRESUMO
Safety of pemetrexed mono-therapy in elderly patients with non-small-cell lung cancer was examined between May 2009 and April 2010 at Kobe City Medical Center General Hospital . The numbers of non-elderly and elderly(over 70 years old)patients were 14 and 19, respectively. Rates of neutropenia over Grade 3 were 14. 3% in the non-elderly group, and 36. 8% in the elderly group(p=0. 297). However, febrile neutropenia was only seen in one case in each group(p=0. 606), and no treatment-related death was observed. Although the rates of rash appearance were 28. 6% and 36. 8%(p=0. 347)for the non-elderly and the elderly, respectively, most rashes were relieved by steroids. From these results, pemetrexed mono-therapy is considered one of the applicable regimens for elderly patients.
Assuntos
Antimetabólitos Antineoplásicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Glutamatos/uso terapêutico , Guanina/análogos & derivados , Neoplasias Pulmonares/tratamento farmacológico , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Antimetabólitos Antineoplásicos/efeitos adversos , Feminino , Glutamatos/efeitos adversos , Guanina/efeitos adversos , Guanina/uso terapêutico , Humanos , Masculino , Pessoa de Meia-Idade , PemetrexedeRESUMO
A 74-year-old woman diagnosed with poorly-differentiated neuroendocrine carcinoma originating from the ascending colon was referred to our hospital. She had felt anorexia, abdominal pains and her (ECOG) performance status was 3. Her CT scan showed that some abdominal lymph nodes were swelling and that there were many metastatic lesions occupying most of the liver. We started chemotherapy with cisplatin and irinotecan according to a regimen for small cell lung cancer. Considering her poor PS, both of the drugs were administered at 30mg/m² twice 4 weeks in the first course of chemotherapy. Her anorexia and abdominal pains immediately disappeared, and CT scan showed that all of the metastases were decreased in size. After 4 courses, however, some of the metastatic lesions were increased in size. She died 8 months after diagnosis. The tumor marker doubling time was 17 days.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Neuroendócrino/tratamento farmacológico , Colo Ascendente/patologia , Neoplasias Hepáticas/tratamento farmacológico , Idoso , Camptotecina/administração & dosagem , Camptotecina/análogos & derivados , Carcinoma Neuroendócrino/patologia , Diferenciação Celular , Cisplatino/administração & dosagem , Evolução Fatal , Feminino , Humanos , Irinotecano , Neoplasias Hepáticas/secundário , Tomografia Computadorizada por Raios XRESUMO
We report a 53-year-old man with cancer of an unknown primary site with an epidermal growth factor receptor mutation for which gefitinib was effective. In 2007, he complained of left gluteal pain and right cervical lymph node swelling. He was given a diagnosis of adenocarcinoma at the biopsy of the right cervical lymph node. Although metastases of multiple lymph nodes, bone, and bilateral adrenal glands were found, the primary site could not be determined on close examination, resulting in a diagnosis of cancer of unknown primary site(poor prognosis group). He was then treated with systemic chemotherapy. After he showed resistance to chemotherapy, he received gefitinib as third-line therapy because the tumor harbored an epidermal growth factor receptor(EGFR)mutation. Subsequently, multiple metastatic tumors gradually reduced and clinical benefit was observed for a long time.
Assuntos
Adenocarcinoma/tratamento farmacológico , Antineoplásicos/uso terapêutico , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/genética , Mutação , Neoplasias Primárias Desconhecidas/tratamento farmacológico , Quinazolinas/uso terapêutico , Adenocarcinoma/genética , Adenocarcinoma/patologia , Biópsia , Gefitinibe , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Primárias Desconhecidas/genética , Tomografia Computadorizada por Raios XRESUMO
BACKGROUND/AIM: We previously reported the usefulness of aberrant methylation of tumor suppressive miRNAs in bile to discriminate pancreaticobiliary cancers (PBCs) from benign pancreaticobiliary diseases (BD). Here we performed a methylation analysis of plasma miRNAs to identify miRNAs specific for PBCs. PATIENTS AND METHODS: Plasma was collected from 80 patients with pancreatic cancer (PC); 18 with biliary tract cancer (BTC) and 28 with BD. Sequences encoding 3 tumor suppressive miRNAs (miR-200a, -200b, and -1247) were PCR amplified and sequenced, and their methylation rates were determined. RESULTS: The methylation rate of miR-1247 was significantly higher in patients with BTC than in those with BD, and tended to be higher in patients with PC than in those with BD. Furthermore, it was significantly higher in three patients with stages I/II BTC than in those with BD. CONCLUSION: Methylation of miR-1247 in plasma may be useful to distinguish BTC from BD.