Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 1.729
Filtrar
1.
Cancer Treat Rev ; 88: 102064, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32622272

RESUMO

The overexpression of human epidermal growth factor receptor-2 (HER2) results in a biologically and clinically aggressive breast cancer (BC) subtype. Since the introduction of anti-HER2 targeted agents, survival rates of patients with HER2-positive metastatic BC have dramatically improved. Currently, although the treatment decision process in metastatic BC is primarily based on HER2 and hormone-receptor (HR) status, a rapidly growing body of data suggests that several other sources of biological heterogeneity may characterize HER2-positive metastatic BC. Moreover, pivotal clinical trials of new anti-HER2 antibody-drug conjugates showed encouraging results in HER2-low metastatic BC, thus leading to the possibility, in the near future, to expand the pool of patients suitable for HER2-targeted treatments. The present review summarizes and puts in perspective available evidence on biomarkers that hold the greatest promise to become potentially useful tools for optimizing HER2-positive metastatic BC patients' prognostic stratification and treatment in the next future. These biomarkers include HER2 levels and heterogeneity, HER3, intrinsic molecular subtypes by PAM50 analysis, DNA mutations, and immune-related factors. Molecular discordance between primary and metastatic tumors is also discussed.


Assuntos
Neoplasias da Mama/metabolismo , Receptor ErbB-2/metabolismo , Receptores de Superfície Celular/metabolismo , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais/biossíntese , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/enzimologia , Neoplasias da Mama/genética , Feminino , Humanos , Metástase Neoplásica , Ensaios Clínicos Controlados Aleatórios como Assunto , Receptor ErbB-2/biossíntese , Receptor ErbB-2/genética , Receptor ErbB-3/biossíntese , Receptor ErbB-3/genética , Receptor ErbB-3/metabolismo
2.
Cancer Sci ; 111(6): 2123-2131, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32248641

RESUMO

HER2-targeting antibodies (trastuzumab, pertuzumab) and a HER2-directed antibody-drug conjugate (trastuzumab emtansine: T-DM1) are used for the treatment of HER2-overexpressing breast cancer. However, these treatments eventually become ineffective due to acquired resistance and there is an urgent need for alternative therapies. TAS0728 is a small-molecule, irreversible selective HER2 kinase inhibitor. In the present study, we established new in vivo models of cancer resistance by continuous exposure to a combination of trastuzumab and pertuzumab or to T-DM1 for evaluating the effect of TAS0728 on HER2 antibody-resistant populations. Treatment with trastuzumab and pertuzumab or with T-DM1 initially induced tumor regression in NCI-N87 xenografts. However, tumor regrowth during treatment indicated loss of drug effectiveness. In tumors with acquired resistance to trastuzumab and pertuzumab or to T-DM1, HER2-HER3 phosphorylation was retained. Switching to TAS0728 resulted in a significant anti-tumor effect associated with HER2-HER3 signal inhibition. No alternative receptor tyrosine kinase activation was observed in these resistant tumors. Furthermore, in a patient-derived xenograft model derived from breast cancer refractory to both trastuzumab/pertuzumab and T-DM1, TAS0728 exerted a potent anti-tumor effect. These results suggest that tumors with acquired resistance to trastuzumab and pertuzumab and to T-DM1 are still dependent on oncogenic HER2-HER3 signaling and are vulnerable to HER2 signal inhibition by TAS0728. These results provide a rationale for TAS0728 therapy for breast cancers that are refractory to established anti-HER2 therapies.


Assuntos
Neoplasias da Mama/patologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Inibidores de Proteínas Quinases/farmacologia , Receptor ErbB-2/antagonistas & inibidores , Ado-Trastuzumab Emtansina/farmacologia , Animais , Anticorpos Monoclonais Humanizados/farmacologia , Antineoplásicos/farmacologia , Neoplasias da Mama/metabolismo , Feminino , Humanos , Camundongos , Camundongos Nus , Receptor ErbB-3/metabolismo , Transdução de Sinais/efeitos dos fármacos , Trastuzumab/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto
3.
Life Sci ; 251: 117634, 2020 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-32251632

RESUMO

Neuregulin-1ß (NRG-1) is a membrane-bound or secreted growth and differentiation factor that mediates its action by binding to ErbB receptors. Circulating levels of NRG-1 are characterized by large inter-individual variability with the range of absolute values covering two orders of magnitude, from hundreds to tens of thousands of picograms per milliliter of blood. NRG-1 signaling via ErbB receptors contributes to the cell survival and downregulation of the inflammatory response. A higher level of circulating NRG-1 may indicate increased shedding of membrane-bound NRG-1, which in turn can contribute to better protection against cardiovascular stress or injury. However, it is unknown whether circulating NRG-1 can induce activation of ErbB receptors. In the current study, we performed an analysis of circulating NRG-1 functional activity using a cell-based ELISA measuring phosphorylation of ErbB3 induced by blood plasma obtained from healthy donors. We found high levels of ErbB3 activating activity in human plasma. No correlations were found between the levels of circulating NRG-1 and plasma ErbB3 activating activity. To determine the direct effect of circulating NRG-1, we incubated plasma with neutralizing antibody, which prevented the stimulatory effect of recombinant NRG-1 on activation of ErbB3. No effect of the neutralizing antibody was found on plasma-induced phosphorylation of ErbB3. We also found that a significant portion of circulating NRG-1 is comprised of full-length NRG-1 associated with large extracellular vesicles. Our results demonstrate that circulating NRG-1 does not contribute to plasma-induced ErbB3 activating activity and emphasizes the importance of functional testing of NRG-1 proteins in biological samples.


Assuntos
Sobrevivência Celular/fisiologia , Neuregulina-1/metabolismo , Receptor ErbB-3/metabolismo , Adulto , Idoso , Anticorpos Neutralizantes/imunologia , Regulação para Baixo , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fosforilação
4.
Int J Radiat Oncol Biol Phys ; 106(5): 1039-1051, 2020 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-31959545

RESUMO

PURPOSE: The outcome of locally advanced cervical cancer (LACC) is dismal. Biomarkers are needed to individualize treatments and to improve patient outcomes. Here, we investigated whether coexpression of epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 3 (HER3) could be an outcome prognostic biomarker, and whether targeting both EGFR and HER3 with a dual antibody (MEHD7945A) enhanced ionizing radiation (IR) efficacy. METHODS AND MATERIALS: Expression of EGFR and HER3 was evaluated by immunohistochemistry in cancer biopsies (n = 72 patients with LACC). The antitumor effects of the MEHD7945A and IR combotherapy were assessed in 2 EGFR- and HER3-positive cervical cancer cell lines (A431 and CaSki) and in A431 cell xenografts. The mechanisms involved in tumor cell radiosensitization were also studied. The interaction of MEHD7945A, IR, and cisplatin was evaluated using dose-response matrix data. RESULTS: EGFR and HER3 were coexpressed in only in 7 of the 22 biopsies of FIGO IVB cervix cancer. The median overall survival was 14.6 months and 23.1 months in patients with FIGO IVB tumors that coexpressed or did not coexpress EGFR and HER3, respectively. In mice xenografted with A431 (squamous cell carcinoma) cells, MEHD7945A significantly increased IR response by reducing tumor growth and increasing cleaved caspase-3 expression. In A431 and CaSki cells, the combotherapy increased DNA damage and cell death, particularly immunogenic cell death, and decreased survival by inhibiting the MAPK and AKT pathways. An additive effect was observed when IR, MEHD7945A, and cisplatin were combined. CONCLUSIONS: Targeting EGFR and HER3 with a specific dual antibody enhanced IR efficacy. These preliminary results and the prognostic value of EGFR and HER3 coexpression should be confirmed in a larger sample.


Assuntos
Receptores ErbB/imunologia , Imunoglobulina G/imunologia , Receptor ErbB-3/imunologia , Neoplasias do Colo do Útero/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Linhagem Celular Tumoral , Proliferação de Células/efeitos da radiação , Sobrevivência Celular/imunologia , Sobrevivência Celular/efeitos da radiação , Transformação Celular Neoplásica , Terapia Combinada , Dano ao DNA , Receptores ErbB/metabolismo , Feminino , Regulação Neoplásica da Expressão Gênica/imunologia , Regulação Neoplásica da Expressão Gênica/efeitos da radiação , Humanos , Imunoglobulina G/uso terapêutico , Camundongos , Pessoa de Meia-Idade , Receptor ErbB-3/metabolismo , Estudos Retrospectivos , Transdução de Sinais/imunologia , Transdução de Sinais/efeitos da radiação , Neoplasias do Colo do Útero/imunologia , Neoplasias do Colo do Útero/metabolismo , Neoplasias do Colo do Útero/radioterapia
5.
Gynecol Oncol ; 156(3): 552-560, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31902686

RESUMO

OBJECTIVE: Mucinous ovarian carcinoma (MOC) is an uncommon ovarian cancer histotype that responds poorly to conventional chemotherapy regimens. Although long overall survival outcomes can occur with early detection and optimal surgical resection, recurrent and advanced disease are associated with extremely poor survival. There are no current guidelines specifically for the systemic management of recurrent MOC. We analyzed data from a large cohort of women with MOC to evaluate the potential for clinical utility from a range of systemic agents. METHODS: We analyzed gene copy number (n = 191) and DNA sequencing data (n = 184) from primary MOC to evaluate signatures of mismatch repair deficiency and homologous recombination deficiency, and other genetic events. Immunohistochemistry data were collated for ER, CK7, CK20, CDX2, HER2, PAX8 and p16 (n = 117-166). RESULTS: Molecular aberrations noted in MOC that suggest a match with current targeted therapies include amplification of ERBB2 (26.7%) and BRAF mutation (9%). Observed genetic events that suggest potential efficacy for agents currently in clinical trials include: KRAS/NRAS mutations (66%), TP53 missense mutation (49%), RNF43 mutation (11%), ARID1A mutation (10%), and PIK3CA/PTEN mutation (9%). Therapies exploiting homologous recombination deficiency (HRD) may not be effective in MOC, as only 1/191 had a high HRD score. Mismatch repair deficiency was similarly rare (1/184). CONCLUSIONS: Although genetically diverse, MOC has several potential therapeutic targets. Importantly, the lack of response to platinum-based therapy observed clinically corresponds to the lack of a genomic signature associated with HRD, and MOC are thus also unlikely to respond to PARP inhibition.


Assuntos
Adenocarcinoma Mucinoso/genética , Adenocarcinoma Mucinoso/terapia , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/terapia , Adenocarcinoma Mucinoso/metabolismo , Adenocarcinoma Mucinoso/patologia , Idoso , Estudos de Coortes , Reparo de Erro de Pareamento de DNA , Feminino , Recombinação Homóloga , Humanos , Imuno-Histoquímica , Mutação , Estadiamento de Neoplasias , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/patologia , Receptor ErbB-2/genética , Receptor ErbB-3/genética
6.
DNA Cell Biol ; 39(3): 398-403, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31976761

RESUMO

Diabetic retinopathy (DR) is considered a main cause for vision loss in diabetes. To our knowledge, there were no studies on the association of genetic variants with DR in Chinese Hui nationality. In our research, 34 single nucleotide polymorphisms (SNPs) that were reported to be associated with DR in other ethnics were genotyped in 123 subjects with DR and 12 subjects without DR among Chinese Hui population using MassARRAY system. Association analysis performed by PLINK showed three SNP loci rs2300782, rs2292239, and rs10491034 were correlated with DR incidence. Furthermore, the genotype frequency analysis and association analysis of SNP with DR stage revealed the GT and TT genotypes of rs2292239, CC genotype of rs2300782, and GG genotype of rs10491034 were risk genotypes and associated with the severity of DR, which may be helpful for the study of DR susceptibility in Chinese Hui population. Our study indicates the rs2300782 of gene CAMK4, rs2292239 of gene ERBB3, and rs10491034 of gene ARHGAP22 are associated with DR incidence and severity among Chinese Hui population.


Assuntos
Proteína Quinase Tipo 4 Dependente de Cálcio-Calmodulina/genética , Retinopatia Diabética/genética , Proteínas Ativadoras de GTPase/genética , Polimorfismo de Nucleotídeo Único , Receptor ErbB-3/genética , Idoso , China , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
7.
Cancer Sci ; 111(1): 137-147, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31724799

RESUMO

As a member of the epidermal growth factor receptor (EGFR) family, ERBB3 plays an essential role in development and disease independent of inherently inactive kinase domain. Recently, ERBB3 has been found to bind to ATP and has catalytic activity in vitro. However, the biological function of ERBB3 kinase activity remains elusive in vivo. Here we have identified the physiological function of inactivated ERBB3 kinase activity by creating Erbb3-K740M knockin mice in which ATP cannot bind to ERBB3. Unlike Erbb3 knockout mice, kinase-inactive Erbb3K740M homozygous mice were born in Mendelian ratios and showed normal development. After dextran sulfate sodium-induced colitis, the kinase-inactive Erbb3 mutant mice showed normal recovery. However, the outgrowth of ileal organoids by neuregulin-1 treatment was more attenuated in Erbb3 mutant mice than in WT mice. Moreover, in combination with the ApcMin mouse, the proportion of polyps less than 1 mm in diameter in mutant mice was higher than in control mice and an increase in the number of apoptotic cells was observed in polyps from mutant mice compared with polyps from control mice. Taken together, the ERBB3 kinase activity contributes to the outgrowth of ileal organoids and intestinal tumorigenesis, and the development of ERBB3 kinase inhibitors, including epidermal growth factor receptor family members, can be a potential way to target colorectal cancer.


Assuntos
Carcinogênese/metabolismo , Carcinogênese/patologia , Intestinos/patologia , Organoides/metabolismo , Organoides/patologia , Receptor ErbB-3/metabolismo , Animais , Apoptose/efeitos dos fármacos , Apoptose/fisiologia , Carcinogênese/efeitos dos fármacos , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Intestinos/efeitos dos fármacos , Camundongos , Camundongos Knockout , Organoides/efeitos dos fármacos , Fosforilação/efeitos dos fármacos , Fosforilação/fisiologia , Pólipos/tratamento farmacológico , Pólipos/patologia , Inibidores de Proteínas Quinases/farmacologia
8.
Biochim Biophys Acta Mol Cell Res ; 1867(4): 118625, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31862538

RESUMO

Despite recent advances in treatment of non-small cell lung cancer (NSCLC), prognosis still remains poor and new therapeutic approaches are needed. Studies demonstrate the importance of the EGFR/HER-receptor family in NSCLC growth, as well as that of other tumors. Recently, HER3 is receiving increased attention because of its role in drug resistance and aggressive growth. Activation of overexpressed G-protein-coupled receptors (GPCR) can also initiate growth by transactivating EGFR/HER-family members. GPCR transactivation of EGFR has been extensively studied, but little is known of its ability to transactivate other EGFR/HER-members, especially HER3. To address this, we studied the ability of bombesin receptor (BnR) activation to transactivate all EGFR/HER-family members and their principal downstream signaling cascades, the PI3K/Akt- and MAPK/ERK-pathways, in human NSCLC cell-lines. In all three cell-lines studied, which possessed EGFR, HER2 and HER3, Bn rapidly transactivated EGFR, HER2 and HER3, as well as Akt and ERK. Immunoprecipitation studies revealed Bn-induced formation of both HER3/EGFR- and HER3/HER2-heterodimers. Specific EGFR/HER3 antibodies or siRNA-knockdown of EGFR and HER3, demonstrated Bn-stimulated activation of EGFR/HER members is initially through HER3, not EGFR. In addition, specific inhibition of HER3, HER2 or MAPK, abolished Bn-stimulated cell-growth, while neither EGFR nor Akt inhibition had an effect. These results show HER3 transactivation mediates all growth effects of BnR activation through MAPK. These results raise the possibility that targeting HER3 alone or with GPCR activation and its signal cascades, may be a novel therapeutic approach in NSCLC. This is especially relevant with the recent development of HER3-blocking antibodies.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/metabolismo , Proliferação de Células , Neoplasias Pulmonares/metabolismo , Sistema de Sinalização das MAP Quinases , Receptor ErbB-3/metabolismo , Receptores da Bombesina/metabolismo , Bombesina/metabolismo , Linhagem Celular Tumoral , Humanos , Neuregulina-1/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptores da Bombesina/genética
9.
Phytomedicine ; 66: 153109, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31790894

RESUMO

BACKGROUND: Lung cancer is one of the most common malignancies worldwide. To treat lung cancer, various anticancer drugs were developed and tested, but they failed because of drug resistance. In the present study, we tested herbal medicines, such as TK and CuD, as anticancer drugs to decrease side effects and resistance. METHODS: Cell viability was measured by an MTT assay. Analysis of cell cycle arrest was performed by flow cytometry. Induction of apoptosis by cucurbitacin D was measured by an annexin V-FITC/PI assay. We performed RTK kit analysis. Levels of p-ErbB3, p-STAT3, p-NF-κB, and caspases were measured by western blot analysis. Nuclear staining of ErbB3 was measured by immunocytochemistry. Transcriptional activity of STAT3 and NF-κB was detected by STAT3 and NF-κB luciferase reporter gene assays. RESULTS: We found a synergistic effect of TK with CDDP and PXD in primary culture of human NSCLC tumor cells. The combination of CDDP/PXD and TK or CuD inhibited the proliferation of H1299 cells. The combination of CDDP/PXD and TK or CuD induced sub-G1 and G2/M cell cycle arrest in H1299 cells. The combination of CDDP/PXD and TK or CuD induced apoptosis, regulated apoptotic molecules, caused morphological changes and inhibited colony formation in H1299 cells. We found that TK suppresses p-ErbB3 expression and signaling. The combination of CDDP/PXD and TK or CuD inhibited p-AKT, p-Erk, and p-JNK signaling and suppressed Stat3 and NF-κB transcriptional activity in H1299 cells. More importantly, the combination of CDDP/PXD and TK or CuD inhibited p-ErbB3 and downstream molecules in H1299 cells. The combination of CDDP/PXD and TK or CuD inhibited ErbB2/ErbB3 dimerization. Our results clearly demonstrate that the synergistic effect of CDDP/PXD and TK or CuD inhibits cell growth and induces apoptosis by inhibiting ErbB3 signaling. CONCLUSION: The combination of CDDP/PXD and TK or CuD decreases cell proliferation and induces apoptosis by inhibiting ErbB3 signaling in H1299 lung cancer cells. TK or CuD could be useful as a compound to treat lung cancer. Additionally, targeting ErbB3 may also be useful for treating lung cancer.


Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Cisplatino/farmacologia , Neoplasias Pulmonares/tratamento farmacológico , Pemetrexede/farmacologia , Trichosanthes/química , Caspases/metabolismo , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Sinergismo Farmacológico , Medicamentos de Ervas Chinesas , Humanos , Receptor ErbB-3/metabolismo , Transdução de Sinais/efeitos dos fármacos , Triterpenos/administração & dosagem
10.
Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi ; 35(10): 938-943, 2019 Oct.
Artigo em Chinês | MEDLINE | ID: mdl-31814571

RESUMO

Objective To express, purify and identify the single-chain fragment variable (scFv) against human epidermal growth factor receptor 3 (HER3). Methods We searched NCBI for the light chain sequence and heavy chain sequence of anti-HER3 mAb LJM716 to construct the gene of scFv against HER3. The recombinant expression vector pGAPZαA-anit-HER3-scFv was constructed using the constitutive expression vector pGAPZαA and then electro-transformed into Pichia Pastoris X-33 to screen the strains with high expression of the protein of interest. After shaking flask fermentation, the supernatant was purified by hydrophobic chromatography and metal ion affinity chromatography. The purified product was identified by Western blotting and ELISA. Results The anti-HER3-scFv gene was successfully constructed and the strains with high expression of anti-HER3-scFv were obtained. The anti-HER3-scFv was purified to a purity of more than 95% by two-step chromatography, and the purified yield was 192 mg/L. Western blotting showed that the anti-HER3-scFv was correctly expressed and ELISA indicated that anti-HER3-scFv could specifically recognize HER3. Conclusion The anti-HER3-scFv has been successfully prepared.


Assuntos
Anticorpos Monoclonais , Receptor ErbB-3/imunologia , Anticorpos de Cadeia Única , Western Blotting , Ensaio de Imunoadsorção Enzimática , Humanos
11.
BMC Cancer ; 19(1): 959, 2019 Oct 16.
Artigo em Inglês | MEDLINE | ID: mdl-31619200

RESUMO

BACKGROUND: HER3 mediates drug resistance against epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs), resulting in tumor relapse in lung cancers. Previously, we demonstrated that EGFR induces HER3 overexpression, which facilitates the formation of cancer stem-like tumorspheres. However, the cellular mechanism through which EGFR regulates HER3 expression remains unclear. We hypothesized that EGFR downstream of STAT3 participates in HER3 expression because STAT3 contributes to cancer stemness and survival of EGFR-TKI resistant cancers. METHODS: First, RNAseq was used to uncover potential genes involved in the formation of lung cancer HCC827-derived stem-like tumorspheres. EGFR-positive lung cancer cell lines, including HCC827, A549, and H1975, were individually treated with a panel containing 172 therapeutic agents targeting stem cell-associated genes to search for potential agents that could be applied against EGFR-positive lung cancers. In addition, gene knockdown and RNAseq were used to investigate molecular mechanisms through which STAT3 regulates tumor progression and the survival in lung cancer. RESULTS: BBI608, a STAT3 inhibitor, was a potential therapeutic agent that reduced the cell viability of EGFR-positive lung cancer cell lines. Notably, the inhibitory effects of BBI608 were similar with those associated with YM155, an ILF3 inhibitor. Both compounds reduced G9a-mediated HER3 expression. We also demonstrated that STAT3 upregulated G9a to silence miR-145-5p, which exacerbated HER3 expression in this study. CONCLUSIONS: The present study revealed that BBI608 could eradicate EGFR-positive lung cancers and demonstrated that STAT3 enhanced the expression of HER3 through miR-145-5p repression by G9a, indicating that STAT3 is a reliable therapeutic target against EGFR-TKI-resistant lung cancers.


Assuntos
Antígenos de Histocompatibilidade/metabolismo , Histona-Lisina N-Metiltransferase/metabolismo , Neoplasias Pulmonares/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Receptor ErbB-3/metabolismo , Fator de Transcrição STAT3/metabolismo , Células A549 , Animais , Benzofuranos/farmacologia , Movimento Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/metabolismo , Técnicas de Silenciamento de Genes , Antígenos de Histocompatibilidade/genética , Histona-Lisina N-Metiltransferase/genética , Humanos , Imidazóis/farmacologia , Neoplasias Pulmonares/patologia , Masculino , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , MicroRNAs/genética , MicroRNAs/metabolismo , Naftoquinonas/farmacologia , Proteínas do Fator Nuclear 90/antagonistas & inibidores , Proteínas do Fator Nuclear 90/genética , Inibidores de Proteínas Quinases/efeitos adversos , Receptor ErbB-3/antagonistas & inibidores , Fator de Transcrição STAT3/antagonistas & inibidores , Fator de Transcrição STAT3/genética , Ensaios Antitumorais Modelo de Xenoenxerto
12.
Eur J Pharm Biopharm ; 145: 42-53, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31626948

RESUMO

The delivery of aptamer modified therapeutic moieties to specific tissue sites has become one of the major therapeutic choices to reduce the toxicity of inhibitory drugs. Bearing this in mind, the current study was designed using sorafenib (SFB) encapsulated microparticles (MP) prepared with biodegradable poly (D, L-lactic-co-glycolic acid) (PLGA) copolymer. The surfaces of these microparticles were modified with RNA aptamer having a binding affinity towards ErbB3 receptors. SFB-loaded MP (MPS) were prepared by o/w solvent evaporation method and the surface was coupled with the amino group of aptamer by EDC/NHS chemistry. Physiochemical investigations were done by dynamic light scattering, scanning electron microscopy and FTIR. In vitro apoptosis assay, cell viability assay and metastatic progression showed a significant decrease (p < 0.001) in vitro cell viability for MPS and MPS-Apt as compared to MP. The synergistic combination of SFB and aptamer also decreased the metastatic progression of cells for an extended period. Microparticles were also evaluated for in vivo toxicity in female BALB/c mice. It was evident that the presence of aptamer decreased the generalized toxicity of MPS-Apt, as measured by mean body weight loss and blood profiles, keeping all the blood formed elements level within acceptable limits. The histopathological investigations showed some necrotic and pyknotic bodies. In a similar fashion, liver function test and renal function tests showed pronounced effects of formulations on vital organs.


Assuntos
Receptor ErbB-3/antagonistas & inibidores , Sorafenibe/toxicidade , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Composição de Medicamentos/métodos , Sistemas de Liberação de Medicamentos/métodos , Feminino , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Microesferas , Tamanho da Partícula , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Polímeros/química , Solventes/química , Sorafenibe/química
13.
Nucleic Acids Res ; 47(21): 11020-11043, 2019 12 02.
Artigo em Inglês | MEDLINE | ID: mdl-31617560

RESUMO

RNA interference represents a potent intervention for cancer treatment but requires a robust delivery agent for transporting gene-modulating molecules, such as small interfering RNAs (siRNAs). Although numerous molecular approaches for siRNA delivery are adequate in vitro, delivery to therapeutic targets in vivo is limited by payload integrity, cell targeting, efficient cell uptake, and membrane penetration. We constructed nonviral biomaterials to transport small nucleic acids to cell targets, including tumor cells, on the basis of the self-assembling and cell-penetrating activities of the adenovirus capsid penton base. Our recombinant penton base chimera contains polypeptide domains designed for noncovalent assembly with anionic molecules and tumor homing. Here, structural modeling, molecular dynamics simulations, and functional assays suggest that it forms pentameric units resembling viral capsomeres that assemble into larger capsid-like structures when combined with siRNA cargo. Pentamerization forms a barrel lined with charged residues mediating pH-responsive dissociation and exposing masked domains, providing insight on the endosomolytic mechanism. The therapeutic impact was examined on tumors expressing high levels of HER3/ErbB3 that are resistant to clinical inhibitors. Our findings suggest that our construct may utilize ligand mimicry to avoid host attack and target the siRNA to HER3+ tumors by forming multivalent capsid-like structures.


Assuntos
Portadores de Fármacos/uso terapêutico , Nanopartículas/uso terapêutico , RNA Interferente Pequeno/farmacologia , Receptor ErbB-3/antagonistas & inibidores , Proteínas Recombinantes/uso terapêutico , Animais , Proteínas do Capsídeo/química , Linhagem Celular Tumoral , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Neuregulina-1/química , Interferência de RNA
14.
BMC Cancer ; 19(1): 880, 2019 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-31488078

RESUMO

BACKGROUND: Abrogation of growth factor-dependent signaling represents an effective therapeutic strategy for patients with colorectal cancer (CRC). Here we evaluated the effectiveness of targeting the epidermal growth factor (EGF) receptors HER-2 and HER-3 in the three cell lines LS513, LS1034 and SW837. METHODS: Treatment with HER-2-specific antibodies trastuzumab and pertuzumab resulted in a mild reduction of cellular viability. In contrast, the antibody-drug conjugate T-DM1 mediated a strong and dose-dependent decrease of viability and Akt phosphorylation. RESULTS: The most striking effects were observed with the dual tyrosine kinase inhibitor lapatinib, and the Pan-ErbB inhibitor afatinib. Selectively, the effect of EGF receptor inhibition was augmented by a combination with 5-fluorouracil and oxaliplatin. Finally, high expression of HER-3 was detected in 121 of 172 locally advanced rectal cancers (70.3%). In conclusion, inhibition of EGF receptors effectively blocks downstream signaling and significantly impairs viability of CRC cells. However, the effectiveness of receptor inhibition highly depends on the inhibitors' mode of action, as targeting HER-2 alone is not sufficient. CONCLUSION: Since HER-2 and HER-3 are expressed in a relevant number of patients, targeting both receptors may represent a promising therapeutic strategy for CRC.


Assuntos
Neoplasias Colorretais/metabolismo , Terapia de Alvo Molecular/métodos , Receptor ErbB-2/antagonistas & inibidores , Receptor ErbB-3/antagonistas & inibidores , Afatinib/farmacologia , Anticorpos Monoclonais Humanizados/farmacologia , Células CACO-2 , Sobrevivência Celular/efeitos dos fármacos , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/patologia , Quimioterapia Combinada , Fluoruracila/farmacologia , Células HCT116 , Células HT29 , Humanos , Lapatinib/farmacologia , Oxaliplatina/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Receptor ErbB-2/metabolismo , Receptor ErbB-3/metabolismo , Transdução de Sinais/efeitos dos fármacos , Trastuzumab/farmacologia
15.
Int J Gynecol Cancer ; 29(7): 1141-1147, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31420414

RESUMO

INTRODUCTION: The PENELOPE trial evaluated pertuzumab added to chemotherapy for biomarker-selected platinum-resistant ovarian cancer. As previously reported, pertuzumab did not statistically significantly improve progression-free survival (primary end point: HR 0.74, 95% CI 0.50 to 1.11), although results in the paclitaxel and gemcitabine cohorts suggested activity. Here, we report final overall survival and patient-reported outcomes. PATIENTS AND METHODS: Eligible patients had ovarian carcinoma that progressed during/within 6 months of completing ≥4 platinum cycles, low tumor human epidermal growth factor receptor 3 (HER3) mRNA expression, and ≤2 prior chemotherapy lines. Investigators selected single-agent topotecan, gemcitabine or weekly paclitaxel before patients were randomized to either placebo or pertuzumab (840→420 mg every 3 weeks), stratified by selected chemotherapy, prior anti-angiogenic therapy, and platinum-free interval. Final overall survival analysis (key secondary end point) was pre-specified after 129 deaths. Patient-reported outcomes (secondary end point) were assessed at baseline and every 9 weeks until disease progression. RESULTS: At database lock (June 9, 2016), 130 (83%) of 156 randomized patients had died. Median follow-up was 27 months in the pertuzumab arm versus 26 months in the control arm. In the intent-to-treat population there was no overall survival difference between treatment arms (stratified HR 0.90, 95% CI 0.61 to 1.32; p=0.60). Results in subgroups defined by stratification factors indicated heterogeneity similar to previous progression-free survival results. Updated safety was similar to previously published results. Compliance with patient-reported outcomes questionnaire completion was >75% for all validated patient-reported outcomes measures. Pertuzumab demonstrated neither beneficial nor detrimental effects on patient-reported outcomes compared with placebo, except for increased diarrhea symptoms. DISCUSSION: Consistent with the primary results, adding pertuzumab to chemotherapy for low tumor HER3 mRNA-expressing platinum-resistant ovarian cancer did not improve overall survival, but showed trends in some cohorts. Except for increased diarrhea symptoms, pertuzumab had no impact on patient-reported outcomes. ClinicalTrials.gov: ClinicalTrials.gov: NCT01684878.


Assuntos
Anticorpos Monoclonais Humanizados/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Epitelial do Ovário/tratamento farmacológico , Neoplasias Ovarianas/tratamento farmacológico , RNA Mensageiro/biossíntese , Receptor ErbB-3/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos Imunológicos/administração & dosagem , Carcinoma Epitelial do Ovário/enzimologia , Carcinoma Epitelial do Ovário/genética , Desoxicitidina/administração & dosagem , Desoxicitidina/análogos & derivados , Método Duplo-Cego , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Pessoa de Meia-Idade , Neoplasias Ovarianas/enzimologia , Neoplasias Ovarianas/genética , Paclitaxel/administração & dosagem , Medidas de Resultados Relatados pelo Paciente , Intervalo Livre de Progressão , RNA Mensageiro/genética , Receptor ErbB-3/biossíntese , Topotecan/administração & dosagem
16.
Pathol Res Pract ; 215(10): 152551, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31400925

RESUMO

HER3 and HER4 are tyrosine kinase receptors of the ErbB family that have been detected in several cancers but lack substantial investigation in human meningiomas. In this study, HER3 and -4 expression levels were evaluated as potential biomarkers by immunohistochemistry and explored for association to clinical features in a large series of human meningiomas. 186 primary intracranial meningiomas from adult patients were investigated with antibodies against HER3 and -4 intracellular domains. Tumors were scored with a staining index (SI) based on cytoplasmic/membranous staining intensity and on the percentage of positive cells. SIs were tested for associations with WHO malignancy grade, tumor subtype, localization, and prognosis. HER3 and HER4 were highly expressed in most tumors. Both cytoplasmic and membranous immunoreactivity occurred, and for HER4 nuclear immunoreactivity was observed as well. Non-neoplastic meningeal tissue was not immunoreactive. HER3 and -4 immunoreactivity was not associated with WHO malignancy grade, nor with recurrence or survival in adjusted analyses. Meningiomas of all grades were shown to widely express both HER3 and HER4 receptors. This feature may have diagnostic value since non-neoplastic meninges were not immunoreactive. There was no prognostic significance in adjusted survival analyses.


Assuntos
Regulação Neoplásica da Expressão Gênica , Neoplasias Meníngeas/metabolismo , Meningioma/metabolismo , Receptor ErbB-3/metabolismo , Receptor ErbB-4/metabolismo , Idoso , Biomarcadores Tumorais/metabolismo , Feminino , Humanos , Imuno-Histoquímica , Masculino , Neoplasias Meníngeas/mortalidade , Neoplasias Meníngeas/patologia , Meningioma/mortalidade , Meningioma/patologia , Pessoa de Meia-Idade , Prognóstico , Análise de Sobrevida , Taxa de Sobrevida
17.
Biomed Res Int ; 2019: 7689642, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31467911

RESUMO

Objectives: The purpose of this study was to explore the association between rs2292239 polymorphism in ERBB3 gene and type 1 diabetes (T1D). Methods: A systematic search of studies on the association of rs2292239 polymorphism in ERBB3 gene with T1D susceptibility was conducted in PubMed, Web of science, Elsevier Science Direct, and Cochrane Library. Eventually, 9 published studies were included. The strength of association between rs2292239 polymorphism and T1D susceptibility was assessed by odds ratios (ORs) with its 95% confidence intervals (CIs). Results: A total of 9 case-control studies, consisting of 5369 T1D patients and 6920 controls, were included in the meta-analysis. This meta-analysis showed significant association between ERBB3 rs2292239 polymorphism and T1D susceptibility in overall population (A vs. C, OR: 1.292, 95% CI= 1.224-1.364, P H=0.450, P H is P value for the heterogeneity test). Similar results were found in subgroup analysis by ethnicity. Conclusions: ERBB3 rs2292239 polymorphism is associated with T1D susceptibility and rs2292239-A allele is a risk factor for T1D. However, more large-scale studies are warranted to replicate our findings.


Assuntos
Diabetes Mellitus Tipo 1/genética , Estudos de Associação Genética , Predisposição Genética para Doença , Receptor ErbB-3/genética , Alelos , Diabetes Mellitus Tipo 1/patologia , Genótipo , Humanos , Polimorfismo de Nucleotídeo Único/genética , Fatores de Risco
18.
EMBO Rep ; 20(10): e48058, 2019 10 04.
Artigo em Inglês | MEDLINE | ID: mdl-31468695

RESUMO

Cyclin-dependent kinase 12 (CDK12) has emerged as an effective therapeutic target due to its ability to regulate DNA damage repair in human cancers, but little is known about the role of CDK12 in driving tumorigenesis. Here, we demonstrate that CDK12 promotes tumor initiation as a novel regulator of cancer stem cells (CSCs) and induces anti-HER2 therapy resistance in human breast cancer. High CDK12 expression caused by concurrent amplification of CDK12 and HER2 in breast cancer patients is associated with disease recurrence and poor survival. CDK12 induces self-renewal of breast CSCs and in vivo tumor-initiating ability, and also reduces susceptibility to trastuzumab. Furthermore, CDK12 kinase activity inhibition facilitates anticancer efficacy of trastuzumab in HER2+ tumors, and mice bearing trastuzumab-resistant HER2+ tumor show sensitivity to an inhibitor of CDK12. Mechanistically, the catalytic activity of CDK12 is required for the expression of genes involved in the activation of ErbB-PI3K-AKT or WNT-signaling cascades. These results suggest that CDK12 is a major oncogenic driver and an actionable target for HER2+ breast cancer to replace or augment current anti-HER2 therapies.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Carcinogênese/patologia , Quinases Ciclina-Dependentes/metabolismo , Resistencia a Medicamentos Antineoplásicos , Transdução de Sinais , Trastuzumab/uso terapêutico , Animais , Neoplasias da Mama/enzimologia , Neoplasias da Mama/genética , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cromossomos Humanos Par 17/genética , Quinases Ciclina-Dependentes/antagonistas & inibidores , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Proteínas Substratos do Receptor de Insulina/metabolismo , Camundongos , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Fosfatidilinositol 3-Quinases/metabolismo , Prognóstico , Ligação Proteica/efeitos dos fármacos , Inibidores de Proteínas Quinases/farmacologia , Receptor ErbB-3/metabolismo , Trastuzumab/farmacologia , Regulação para Cima/efeitos dos fármacos , Regulação para Cima/genética , Via de Sinalização Wnt
19.
J Gynecol Oncol ; 30(5): e75, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31328457

RESUMO

OBJECTIVES: Human epidermal growth factor receptor-2 (HER2) and 3 (HER3) belong to the epidermal growth factor receptor (EGFR) family of transmembrane receptor tyrosine kinases. In this study, we assessed HER2/HER3 expression levels in specimens of epithelial ovarian cancer and determined their correlation with clinical features of ovarian cancer. METHODS: Tissue microarrays (TMAs) were prepared from paraffin blocks of 105 ovarian tumour samples. HER2, HER3, PI3K, Akt, p-Akt, mTOR, p-mTOR, S6, and p-S6 expression levels were investigated using immunohistochemistry (IHC). HER2 and HER3 amplifications were determined using in situ hybridization (ISH). The correlation between HER2/3 expression and disease outcome of the patients including surgical outcome, progression-free survival (PFS) and overall survival (OS) was analysed. RESULTS: HER2 positivity was 3.8% by IHC and 5.7% by ISH, whereas that of HER3 was 12.4% and 8.6%, respectively. HER2 status by either IHC or ISH was not related to PFS (p=0.128, 0.168, respectively) and OS (p=0.245, 0.164, respectively). However, the HER3 status determined using fluorescence ISH was associated with poor PFS (p=0.035 on log rank test), which was a significant risk factor even after adjusting other possible risk factors in multivariate analysis (hazard ratio=2.377 [1.18-7.49], p=0.021). Expressions of Akt, p-mTOR, and S6 were also related with poor progression (p=0.008, 0.049, 0.014, respectively). CONCLUSION: HER3 is possibly an independent marker for poor prognosis in individuals with ovarian cancer, as the HER3 signalling pathway is distinct from that of HER2. The possibility of targeted therapy for patients with HER3 alteration in ovarian cancer should be evaluated.


Assuntos
Neoplasias Ovarianas/mortalidade , Receptor ErbB-2/metabolismo , Receptor ErbB-3/metabolismo , Intervalo Livre de Doença , Feminino , Humanos , Pessoa de Meia-Idade , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/cirurgia , Prognóstico , República da Coreia/epidemiologia , Estudos Retrospectivos , Fatores de Risco , Análise Serial de Tecidos
20.
BMC Cancer ; 19(1): 741, 2019 Jul 29.
Artigo em Inglês | MEDLINE | ID: mdl-31357969

RESUMO

BACKGROUND: The overall prognosis of non-small cell lung cancer (NSCLC) is poor, and currently only patients with localized disease are potentially curable. Therefore, preferably non-invasively determined biomarkers that detect NSCLC patients at early stages of the disease are of high clinical relevance. The aim of this study was to identify and validate novel protein markers in plasma using the highly sensitive DNA-assisted multiplex proximity extension assay (PEA) to discriminate NSCLC from other lung diseases. METHODS: Plasma samples were collected from a total of 343 patients who underwent surgical resection for different lung diseases, including 144 patients with lung adenocarcinoma (LAC), 68 patients with non-malignant lung disease, 83 patients with lung metastasis of colorectal cancers and 48 patients with typical carcinoid. One microliter of plasma was analyzed using PEA, allowing detection and quantification of 92 established cancer related proteins. The concentrations of the plasma proteins were compared between disease groups. RESULTS: The comparison between LAC and benign samples revealed significantly different plasma levels for four proteins; CXCL17, CEACAM5, VEGFR2 and ERBB3 (adjusted p-value < 0.05). A multi-parameter classifier was developed to discriminate between samples from LAC patients and from patients with non-malignant lung conditions. With a bootstrap aggregated decision tree algorithm (TreeBagger), a sensitivity of 93% and specificity of 64% was achieved to detect LAC in this risk population. CONCLUSIONS: By applying the highly sensitive PEA, reliable protein profiles could be determined in microliter amounts of plasma. We further identified proteins that demonstrated different plasma concentration in defined disease groups and developed a signature that holds potential to be included in a screening assay for early lung cancer detection.


Assuntos
Adenocarcinoma de Pulmão/sangue , Proteínas Sanguíneas/análise , Carcinoma Pulmonar de Células não Pequenas/sangue , Detecção Precoce de Câncer/métodos , Neoplasias Pulmonares/sangue , Programas de Rastreamento/métodos , Idoso , Antígeno Carcinoembrionário/sangue , Quimiocinas CXC/sangue , Estudos de Coortes , Confiabilidade dos Dados , Feminino , Proteínas Ligadas por GPI/sangue , Humanos , Imunoensaio/métodos , Masculino , Modelos Biológicos , Curva ROC , Receptor ErbB-3/sangue , Sensibilidade e Especificidade , Estatísticas não Paramétricas , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/sangue
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA