Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 32
Filtrar
1.
Cancer Cell ; 42(3): 413-428.e7, 2024 Mar 11.
Artigo em Inglês | MEDLINE | ID: mdl-38402609

RESUMO

KRASG12C inhibitors (adagrasib and sotorasib) have shown clinical promise in targeting KRASG12C-mutated lung cancers; however, most patients eventually develop resistance. In lung patients with adenocarcinoma with KRASG12C and STK11/LKB1 co-mutations, we find an enrichment of the squamous cell carcinoma gene signature in pre-treatment biopsies correlates with a poor response to adagrasib. Studies of Lkb1-deficient KRASG12C and KrasG12D lung cancer mouse models and organoids treated with KRAS inhibitors reveal tumors invoke a lineage plasticity program, adeno-to-squamous transition (AST), that enables resistance to KRAS inhibition. Transcriptomic and epigenomic analyses reveal ΔNp63 drives AST and modulates response to KRAS inhibition. We identify an intermediate high-plastic cell state marked by expression of an AST plasticity signature and Krt6a. Notably, expression of the AST plasticity signature and KRT6A at baseline correlates with poor adagrasib responses. These data indicate the role of AST in KRAS inhibitor resistance and provide predictive biomarkers for KRAS-targeted therapies in lung cancer.


Assuntos
Acetonitrilas , Carcinoma de Células Escamosas , Neoplasias Pulmonares , Piperazinas , Pirimidinas , Animais , Camundongos , Humanos , Proteínas Proto-Oncogênicas p21(ras) , Genes ras , Mutação
2.
Drugs Today (Barc) ; 58(11): 523-530, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36422513

RESUMO

Tyrosine kinase inhibitors (TKIs) have provided great benefit for patients with EGFR-mutant non-small cell lung cancer (NSCLC). While prior TKIs have demonstrated limited efficacy against exon 20 insertion mutations of EGFR (EGFR Ex20Ins), mobocertinib (TAK-788) is designed to specifically inhibit these Ex20Ins mutations. In a phase I/II clinical trial, mobocertinib demonstrated meaningful benefits among a cohort of platinum-pretreated patients with EGFR Ex20Ins mutant NSCLC. For this cohort, the objective response rate was 28% (95% confidence interval [CI], 20%-37%). The median progression-free survival and duration of response were 7.3 months (95% CI, 5.5-9.2) and 17.5 months (95% CI, 7.4-20.3), respectively, both by independent review committee assessment. On the basis of these results, mobocertinib was granted accelerated approval as the first TKI for treatment of this indication by the U.S. Food and Drug Administration (FDA) in 2021. This review summarizes the preclinical development of mobocertinib and the early-phase clinical data leading to its approval and discusses potential directions for mobocertinib's development.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Inibidores de Proteínas Quinases , Humanos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Receptores ErbB/genética , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Mutação , Inibidores de Proteínas Quinases/uso terapêutico , Estados Unidos
3.
Cancer Res ; 81(20): 5311-5324, 2021 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-34380634

RESUMO

No targeted treatments are currently approved for HER2 exon 20 insertion-mutant lung adenocarcinoma patients. Mobocertinib (TAK-788) is a potent irreversible tyrosine kinase inhibitor (TKI) designed to target human epidermal growth factor receptor 2 (HER2/ERBB2) exon 20 insertion mutations. However, the function of mobocertinib on HER2 exon 20 insertion-mutant lung cancer is still unclear. Here we conducted systematic characterization of preclinical models to understand the activity profile of mobocertinib against HER2 exon 20 insertions. In HER2 exon 20 insertion-mutant cell lines, the IC50 of mobocertinib was higher than poziotinib and comparable with or slightly lower than afatinib, neratinib, and pyrotinib. Mobocertinib had the lowest HER2 exon 20 insertion IC50/wild-type (WT) EGFR IC50 ratio, indicating that mobocertinib displayed the best selectivity profile in these models. Also, mobocertinib showed strong inhibitory activity in HER2 exon 20YVMA allograft and patient-derived xenograft models. In genetically engineered mouse models, HER2 exon 20G776>VC lung tumors exhibited a sustained complete response to mobocertinib, whereas HER2 exon 20YVMA tumors showed only partial and transient response. Combined treatment with a second antibody-drug conjugate (ADC) against HER2, ado-trastuzumab emtansine (T-DM1), synergized with mobocertinib in HER2 exon 20YVMA tumors. In addition to the tumor cell autonomous effect, sustained tumor growth control derived from M1 macrophage infiltration and CD4+ T-cell activation. These findings support the ongoing clinical development of mobocertinib (NCT02716116) and provide a rationale for future clinical evaluation of T-DM1 combinational therapy in HER2 exon 20YVMA insertion-mutant lung adenocarcinoma patients. SIGNIFICANCE: This study elucidates the potent inhibitory activity of mobocertinib against HER2 exon 20 insertion-mutant lung cancer and the synergic effect of combined mobocertinib and T-DM1, providing a strong rationale for clinical investigation.


Assuntos
Adenocarcinoma de Pulmão/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Éxons , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Mutação INDEL , Neoplasias Pulmonares/tratamento farmacológico , Receptor ErbB-2/genética , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/patologia , Ado-Trastuzumab Emtansina/administração & dosagem , Animais , Anticorpos Biespecíficos/administração & dosagem , Apoptose , Proliferação de Células , Feminino , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
4.
N Engl J Med ; 384(25): 2382-2393, 2021 06 24.
Artigo em Inglês | MEDLINE | ID: mdl-34161704

RESUMO

BACKGROUND: Clinical trials of the KRAS inhibitors adagrasib and sotorasib have shown promising activity in cancers harboring KRAS glycine-to-cysteine amino acid substitutions at codon 12 (KRASG12C). The mechanisms of acquired resistance to these therapies are currently unknown. METHODS: Among patients with KRASG12C -mutant cancers treated with adagrasib monotherapy, we performed genomic and histologic analyses that compared pretreatment samples with those obtained after the development of resistance. Cell-based experiments were conducted to study mutations that confer resistance to KRASG12C inhibitors. RESULTS: A total of 38 patients were included in this study: 27 with non-small-cell lung cancer, 10 with colorectal cancer, and 1 with appendiceal cancer. Putative mechanisms of resistance to adagrasib were detected in 17 patients (45% of the cohort), of whom 7 (18% of the cohort) had multiple coincident mechanisms. Acquired KRAS alterations included G12D/R/V/W, G13D, Q61H, R68S, H95D/Q/R, Y96C, and high-level amplification of the KRASG12C allele. Acquired bypass mechanisms of resistance included MET amplification; activating mutations in NRAS, BRAF, MAP2K1, and RET; oncogenic fusions involving ALK, RET, BRAF, RAF1, and FGFR3; and loss-of-function mutations in NF1 and PTEN. In two of nine patients with lung adenocarcinoma for whom paired tissue-biopsy samples were available, histologic transformation to squamous-cell carcinoma was observed without identification of any other resistance mechanisms. Using an in vitro deep mutational scanning screen, we systematically defined the landscape of KRAS mutations that confer resistance to KRASG12C inhibitors. CONCLUSIONS: Diverse genomic and histologic mechanisms impart resistance to covalent KRASG12C inhibitors, and new therapeutic strategies are required to delay and overcome this drug resistance in patients with cancer. (Funded by Mirati Therapeutics and others; ClinicalTrials.gov number, NCT03785249.).


Assuntos
Acetonitrilas/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Colorretais/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos/genética , Neoplasias Pulmonares/tratamento farmacológico , Mutação , Piperazinas/uso terapêutico , Proteínas Proto-Oncogênicas p21(ras)/genética , Pirimidinas/uso terapêutico , Neoplasias do Apêndice/tratamento farmacológico , Neoplasias do Apêndice/genética , Carcinoma Pulmonar de Células não Pequenas/genética , Neoplasias Colorretais/genética , Humanos , Neoplasias Pulmonares/genética , Conformação Proteica , Proteínas Proto-Oncogênicas p21(ras)/antagonistas & inibidores , Proteínas Proto-Oncogênicas p21(ras)/ultraestrutura , Piridinas/uso terapêutico
5.
Cancer Discov ; 11(7): 1672-1687, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33632773

RESUMO

Most EGFR exon 20 insertion (EGFRex20ins) driver mutations in non-small cell lung cancer (NSCLC) are insensitive to approved EGFR tyrosine kinase inhibitors (TKI). To address the limitations of existing therapies targeting EGFR-mutated NSCLC, mobocertinib (TAK-788), a novel irreversible EGFR TKI, was specifically designed to potently inhibit oncogenic variants containing activating EGFRex20ins mutations with selectivity over wild-type EGFR. The in vitro and in vivo activity of mobocertinib was evaluated in engineered and patient-derived models harboring diverse EGFRex20ins mutations. Mobocertinib inhibited viability of various EGFRex20ins-driven cell lines more potently than approved EGFR TKIs and demonstrated in vivo antitumor efficacy in patient-derived xenografts and murine orthotopic models. These findings support the ongoing clinical development of mobocertinib for the treatment of EGFRex20ins-mutated NSCLC. SIGNIFICANCE: No oral EGFR-targeted therapies are approved for EGFR exon 20 insertion (EGFRex20ins) mutation-driven NSCLC. Mobocertinib is a novel small-molecule EGFR inhibitor specifically designed to target EGFRex20ins mutants. Preclinical data reported here support the clinical development of mobocertinib in patients with NSCLC with EGFR exon 20 insertion mutations.See related commentary by Pacheco, p. 1617.This article is highlighted in the In This Issue feature, p. 1601.


Assuntos
Compostos de Anilina/uso terapêutico , Antineoplásicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Éxons , Indóis/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Pirimidinas/uso terapêutico , Compostos de Anilina/farmacologia , Animais , Antineoplásicos/farmacologia , Carcinoma Pulmonar de Células não Pequenas/genética , Linhagem Celular Tumoral/efeitos dos fármacos , Receptores ErbB , Humanos , Indóis/farmacologia , Neoplasias Pulmonares/genética , Camundongos , Mutagênese Insercional , Pirimidinas/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto
6.
Clin Cancer Res ; 26(10): 2393-2403, 2020 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-32034078

RESUMO

PURPOSE: Evaluating drug responses using primary patient-derived cells ex vivo represents a potentially rapid and efficient approach to screening for new treatment approaches. Here, we sought to identify neratinib combinations in HER2 mutant non-small cell lung cancer (NSCLC) patient xenograft-derived organotypic spheroids (XDOTS) using a short-term ex vivo system. EXPERIMENTAL DESIGN: We generated two HER2-mutant NSCLC PDX models [DFCI359 (HER2 exon19 755_757LREdelinsRP) and DFCI315 (HER2 exon20 V777_G778insGSP)] and used the PDX tumors to generate XDOTS. Tumor spheroids were grown in a microfluidic device and treated ex vivo with neratinib-based drug combinations. Live/dead quantification was performed by dual-labeling deconvolution fluorescence microscopy. The most efficacious ex vivo combination was subsequently validated in vivo using the DFCI359 and DFCI315 PDXs and a HER2 YVMA genetically engineered mouse model. RESULTS: Both neratinib and afatinib, but not gefitinib, induced cell death in DFCI359 XDOTS. The combinations of neratinib/trastuzumab and neratinib/temsirolimus enhanced the therapeutic benefit of neratinib alone in DFCI315 and DFCI359. The combination of neratinib and trastuzumab in vivo was more effective compared with single-agent neratinib or trastuzumab and was associated with more robust inhibition of HER2 and downstream signaling. CONCLUSIONS: The XDOTS platform can be used to evaluate therapies and therapeutic combinations ex vivo using PDX tumors. This approach may accelerate the identification and clinical development of therapies for targets with no or few existing models and/or therapies.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Mutação , Receptor ErbB-2/genética , Animais , Apoptose/efeitos dos fármacos , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Proliferação de Células/efeitos dos fármacos , Feminino , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Quinolinas/administração & dosagem , Receptor ErbB-2/antagonistas & inibidores , Receptor ErbB-2/metabolismo , Esferoides Celulares , Trastuzumab/administração & dosagem , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
7.
Cancer Immunol Res ; 6(10): 1234-1245, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30087114

RESUMO

KRAS mutation is present in approximately 30% of human lung adenocarcinomas. Although recent advances in targeted therapy have shown great promise, effective targeting of KRAS remains elusive, and concurrent alterations in tumor suppressors render KRAS-mutant tumors even more resistant to existing therapies. Contributing to the refractoriness of KRAS-mutant tumors are immunosuppressive mechanisms, such as increased presence of suppressive regulatory T cells (Treg) in tumors and elevated expression of the inhibitory receptor PD-1 on tumor-infiltrating T cells. Treatment with BET bromodomain inhibitors is beneficial for hematologic malignancies, and they have Treg-disruptive effects in a non-small cell lung cancer (NSCLC) model. Targeting PD-1-inhibitory signals through PD-1 antibody blockade also has substantial therapeutic impact in lung cancer, although these outcomes are limited to a minority of patients. We hypothesized that the BET bromodomain inhibitor JQ1 would synergize with PD-1 blockade to promote a robust antitumor response in lung cancer. In the present study, using Kras+/LSL-G12D ; Trp53L/L (KP) mouse models of NSCLC, we identified cooperative effects between JQ1 and PD-1 antibody. The numbers of tumor-infiltrating Tregs were reduced and activation of tumor-infiltrating T cells, which had a T-helper type 1 (Th1) cytokine profile, was enhanced, underlying their improved effector function. Furthermore, lung tumor-bearing mice treated with this combination showed robust and long-lasting antitumor responses compared with either agent alone, culminating in substantial improvement in the overall survival of treated mice. Thus, combining BET bromodomain inhibition with immune checkpoint blockade offers a promising therapeutic approach for solid malignancies such as lung adenocarcinoma. Cancer Immunol Res; 6(10); 1234-45. ©2018 AACR.


Assuntos
Azepinas/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Proteínas Nucleares/antagonistas & inibidores , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Triazóis/uso terapêutico , Transferência Adotiva , Animais , Carcinoma Pulmonar de Células não Pequenas/imunologia , Citocinas/imunologia , Neoplasias Pulmonares/imunologia , Camundongos Nus , Camundongos Transgênicos , Mutação , Proteínas Proto-Oncogênicas p21(ras)/genética , Linfócitos T/imunologia , Proteína Supressora de Tumor p53/deficiência
8.
Clin Cancer Res ; 24(19): 4854-4864, 2018 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-29945997

RESUMO

Purpose: Despite the challenge to directly target mutant KRAS due to its high GTP affinity, some agents are under development against downstream signaling pathways, such as MEK inhibitors. However, it remains controversial whether MEK inhibitors can boost current chemotherapy in KRAS-mutant lung tumors in clinic. Considering the genomic heterogeneity among patients with lung cancer, it is valuable to test potential therapeutics in KRAS mutation-driven mouse models.Experimental Design: We first compared the pERK1/2 level in lung cancer samples with different KRAS substitutions and generated a new genetically engineered mouse model whose tumor was driven by KRAS G12C, the most common KRAS mutation in lung cancer. Next, we evaluated the efficacy of selumetinib or its combination with chemotherapy, in KRASG12C tumors compared with KRASG12D tumors. Moreover, we generated KRASG12C/p53R270H model to explore the role of a dominant negative p53 mutation detected in patients in responsiveness to MEK inhibition.Results: We determined higher pERK1/2 in KRASG12C lung tumors compared with KRASG12D Using mouse models, we further identified that KRASG12C tumors are significantly more sensitive to selumetinib compared with KrasG12D tumors. MEK inhibition significantly increased chemotherapeutic efficacy and progression-free survival of KRASG12C mice. Interestingly, p53 co-mutation rendered KRASG12C lung tumors less sensitive to combination treatment with selumetinib and chemotherapy.Conclusions: Our data demonstrate that unique KRAS mutations and concurrent mutations in tumor-suppressor genes are important factors for lung tumor responses to MEK inhibitor. Our preclinical study supports further clinical evaluation of combined MEK inhibition and chemotherapy for lung cancer patients harboring KRAS G12C and wild-type p53 status. Clin Cancer Res; 24(19); 4854-64. ©2018 AACR.


Assuntos
Benzimidazóis/administração & dosagem , Neoplasias Pulmonares/tratamento farmacológico , MAP Quinase Quinase Quinase 1/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Proteína Supressora de Tumor p53/genética , Aloenxertos , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Modelos Animais de Doenças , Feminino , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , MAP Quinase Quinase Quinase 1/antagonistas & inibidores , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Masculino , Camundongos , Pessoa de Meia-Idade , Mutação , Células NIH 3T3 , Inibidores de Proteínas Quinases/administração & dosagem
9.
Cancer Res ; 78(13): 3709-3717, 2018 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-29760044

RESUMO

Small-cell lung cancer (SCLC) has the highest malignancy among all lung cancers, exhibiting aggressive growth and early metastasis to distant sites. For 30 years, treatment options for SCLC have been limited to chemotherapy, warranting the need for more effective treatments. Frequent inactivation of TP53 and RB1 as well as histone dysmodifications in SCLC suggest that transcriptional and epigenetic regulations play a major role in SCLC disease evolution. Here we performed a synthetic lethal screen using the BET inhibitor JQ1 and an shRNA library targeting 550 epigenetic genes in treatment-refractory SCLC xenograft models and identified HDAC6 as a synthetic lethal target in combination with JQ1. Combined treatment of human and mouse SCLC cell line-derived xenograft tumors with the HDAC6 inhibitor ricolinostat (ACY-1215) and JQ1 demonstrated significant inhibition of tumor growth; this effect was abolished upon depletion of NK cells, suggesting that these innate immune lymphoid cells play a role in SCLC tumor treatment response. Collectively, these findings suggest a potential new treatment for recurrent SCLC.Significance: These findings identify a novel therapeutic strategy for SCLC using a combination of HDAC6 and BET inhibitors. Cancer Res; 78(13); 3709-17. ©2018 AACR.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Azepinas/farmacologia , Desacetilase 6 de Histona/antagonistas & inibidores , Células Matadoras Naturais/imunologia , Neoplasias Pulmonares/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Proteínas/antagonistas & inibidores , Carcinoma de Pequenas Células do Pulmão/tratamento farmacológico , Triazóis/farmacologia , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Azepinas/uso terapêutico , Linhagem Celular Tumoral , Proliferação de Células , Sinergismo Farmacológico , Desacetilase 6 de Histona/genética , Humanos , Ácidos Hidroxâmicos/farmacologia , Ácidos Hidroxâmicos/uso terapêutico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Camundongos , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/patologia , Pirimidinas/farmacologia , Pirimidinas/uso terapêutico , RNA Interferente Pequeno/metabolismo , Carcinoma de Pequenas Células do Pulmão/genética , Carcinoma de Pequenas Células do Pulmão/patologia , Mutações Sintéticas Letais/genética , Resultado do Tratamento , Triazóis/uso terapêutico , Ensaios Antitumorais Modelo de Xenoenxerto
10.
Nat Med ; 24(5): 638-646, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29686424

RESUMO

Although most activating mutations of epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancers (NSCLCs) are sensitive to available EGFR tyrosine kinase inhibitors (TKIs), a subset with alterations in exon 20 of EGFR and HER2 are intrinsically resistant and lack an effective therapy. We used in silico, in vitro, and in vivo testing to model structural alterations induced by exon 20 mutations and to identify effective inhibitors. 3D modeling indicated alterations restricted the size of the drug-binding pocket, limiting the binding of large, rigid inhibitors. We found that poziotinib, owing to its small size and flexibility, can circumvent these steric changes and is a potent inhibitor of the most common EGFR and HER2 exon 20 mutants. Poziotinib demonstrated greater activity than approved EGFR TKIs in vitro and in patient-derived xenograft models of EGFR or HER2 exon 20 mutant NSCLC and in genetically engineered mouse models of NSCLC. In a phase 2 trial, the first 11 patients with NSCLC with EGFR exon 20 mutations receiving poziotinib had a confirmed objective response rate of 64%. These data identify poziotinib as a potent, clinically active inhibitor of EGFR and HER2 exon 20 mutations and illuminate the molecular features of TKIs that may circumvent steric changes induced by these mutations.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Receptores ErbB/genética , Éxons/genética , Neoplasias Pulmonares/genética , Inibidores de Proteínas Quinases/uso terapêutico , Receptor ErbB-2/genética , Afatinib/farmacologia , Afatinib/uso terapêutico , Animais , Sítios de Ligação , Linhagem Celular , Modelos Animais de Doenças , Resistencia a Medicamentos Antineoplásicos/genética , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Humanos , Camundongos , Mutagênese Insercional/genética , Mutação/genética , Inibidores de Proteínas Quinases/farmacologia , Quinazolinas/farmacologia , Quinazolinas/uso terapêutico , Carga Tumoral
11.
Clin Cancer Res ; 24(11): 2594-2604, 2018 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-29298799

RESUMO

Purpose:HER2 (or ERBB2) aberrations, including both amplification and mutations, have been classified as oncogenic drivers that contribute to 2% to 6% of lung adenocarcinomas. HER2 amplification is also an important mechanism for acquired resistance to EGFR tyrosine kinase inhibitors (TKI). However, due to limited preclinical studies and clinical trials, currently there is still no available standard of care for lung cancer patients with HER2 aberrations. To fulfill the clinical need for targeting HER2 in patients with non-small cell lung cancer (NSCLC), we performed a comprehensive preclinical study to evaluate the efficacy of a third-generation TKI, osimertinib (AZD9291).Experimental Design: Three genetically modified mouse models (GEMM) mimicking individual HER2 alterations in NSCLC were generated, and osimertinib was tested for its efficacy against these HER2 aberrations in vivoResults: Osimertinib treatment showed robust efficacy in HER2wt overexpression and EGFR del19/HER2 models, but not in HER2 exon 20 insertion tumors. Interestingly, we further identified that combined treatment with osimertinib and the BET inhibitor JQ1 significantly increased the response rate in HER2-mutant NSCLC, whereas JQ1 single treatment did not show efficacy.Conclusions: Overall, our data indicated robust antitumor efficacy of osimertinib against multiple HER2 aberrations in lung cancer, either as a single agent or in combination with JQ1. Our study provides a strong rationale for future clinical trials using osimertinib either alone or in combination with epigenetic drugs to target aberrant HER2 in patients with NSCLC. Clin Cancer Res; 24(11); 2594-604. ©2018 AACRSee related commentary by Cappuzzo and Landi, p. 2470.


Assuntos
Acrilamidas/farmacologia , Compostos de Anilina/farmacologia , Antineoplásicos/farmacologia , Carcinoma Pulmonar de Células não Pequenas/genética , Neoplasias Pulmonares/genética , Mutação , Inibidores de Proteínas Quinases/farmacologia , Receptor ErbB-2/genética , Animais , Biomarcadores Tumorais , Carcinoma Pulmonar de Células não Pequenas/diagnóstico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Linhagem Celular Tumoral , Variações do Número de Cópias de DNA , Modelos Animais de Doenças , Éxons , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Imageamento por Ressonância Magnética , Camundongos , Terapia de Alvo Molecular , Receptor ErbB-2/antagonistas & inibidores , Ensaios Antitumorais Modelo de Xenoenxerto
12.
Clin Cancer Res ; 23(22): 6993-7005, 2017 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-28821559

RESUMO

Purpose:KRAS-activating mutations are the most common oncogenic driver in non-small cell lung cancer (NSCLC), but efforts to directly target mutant KRAS have proved a formidable challenge. Therefore, multitargeted therapy may offer a plausible strategy to effectively treat KRAS-driven NSCLCs. Here, we evaluate the efficacy and mechanistic rationale for combining mTOR and WEE1 inhibition as a potential therapy for lung cancers harboring KRAS mutations.Experimental Design: We investigated the synergistic effect of combining mTOR and WEE1 inhibitors on cell viability, apoptosis, and DNA damage repair response using a panel of human KRAS-mutant and wild type NSCLC cell lines and patient-derived xenograft cell lines. Murine autochthonous and human transplant models were used to test the therapeutic efficacy and pharmacodynamic effects of dual treatment.Results: We demonstrate that combined inhibition of mTOR and WEE1 induced potent synergistic cytotoxic effects selectively in KRAS-mutant NSCLC cell lines, delayed human tumor xenograft growth and caused tumor regression in a murine lung adenocarcinoma model. Mechanistically, we show that inhibition of mTOR potentiates WEE1 inhibition by abrogating compensatory activation of DNA repair, exacerbating DNA damage in KRAS-mutant NSCLC, and that this effect is due in part to reduction in cyclin D1.Conclusions: These findings demonstrate that compromised DNA repair underlies the observed potent synergy of WEE1 and mTOR inhibition and support clinical evaluation of this dual therapy for patients with KRAS-mutant lung cancers. Clin Cancer Res; 23(22); 6993-7005. ©2017 AACR.


Assuntos
Proteínas de Ciclo Celular/antagonistas & inibidores , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Mutação , Proteínas Nucleares/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Proteínas Tirosina Quinases/antagonistas & inibidores , Serina-Treonina Quinases TOR/antagonistas & inibidores , Proteínas ras/genética , Animais , Antineoplásicos/farmacologia , Apoptose/genética , Proteína Quinase CDC2/metabolismo , Caspases/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Reparo do DNA , Modelos Animais de Doenças , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Camundongos , Modelos Biológicos , Ensaios Antitumorais Modelo de Xenoenxerto
13.
Nat Med ; 23(9): 1063-1071, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28805820

RESUMO

The bromodomain and extraterminal (BET) family of proteins comprises four members-BRD2, BRD3, BRD4 and the testis-specific isoform BRDT-that largely function as transcriptional coactivators and play critical roles in various cellular processes, including the cell cycle, apoptosis, migration and invasion. BET proteins enhance the oncogenic functions of major cancer drivers by elevating the expression of these drivers, such as c-Myc in leukemia, or by promoting the transcriptional activities of oncogenic factors, such as AR and ERG in prostate cancer. Pathologically, BET proteins are frequently overexpressed and are clinically linked to various types of human cancer; they are therefore being pursued as attractive therapeutic targets for selective inhibition in patients with cancer. To this end, a number of bromodomain inhibitors, including JQ1 and I-BET, have been developed and have shown promising outcomes in early clinical trials. Although resistance to BET inhibitors has been documented in preclinical models, the molecular mechanisms underlying acquired resistance are largely unknown. Here we report that cullin-3SPOP earmarks BET proteins, including BRD2, BRD3 and BRD4, for ubiquitination-mediated degradation. Pathologically, prostate cancer-associated SPOP mutants fail to interact with and promote the degradation of BET proteins, leading to their elevated abundance in SPOP-mutant prostate cancer. As a result, prostate cancer cell lines and organoids derived from individuals harboring SPOP mutations are more resistant to BET-inhibitor-induced cell growth arrest and apoptosis. Therefore, our results elucidate the tumor-suppressor role of SPOP in prostate cancer in which it acts as a negative regulator of BET protein stability and also provide a molecular mechanism for resistance to BET inhibitors in individuals with prostate cancer bearing SPOP mutations.


Assuntos
Resistencia a Medicamentos Antineoplásicos/genética , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Neoplasias da Próstata/genética , Proteínas Repressoras/genética , Fatores de Transcrição/metabolismo , Apoptose , Azepinas , Benzodiazepinas , Proteínas de Ciclo Celular , Proliferação de Células , Proteínas Culina , Células HEK293 , Células HeLa , Humanos , Immunoblotting , Imunoprecipitação , Masculino , Terapia de Alvo Molecular , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/metabolismo , Proteínas Serina-Treonina Quinases , Proteínas de Ligação a RNA , Talidomida/análogos & derivados , Triazóis , Ubiquitinação
14.
PLoS One ; 12(6): e0178530, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28582407

RESUMO

Cardiac fibroblasts (CFs) phenotypic conversion to myofibroblasts (MFs) represents a crucial event in cardiac fibrosis that leads to impaired cardiac function. However, regulation of this phenotypic transformation remains unclear. Here, we showed that sirtuin-7 (Sirt7) plays an important role in the regulation of MFs differentiation. Sirt7 expression and phosphorylation were upregulated in CFs upon angiotensin-II (Ang-II) stimulation. Sirt7 depletion by siRNA in CFs resulted in decreased cell proliferation and extracellular matrix (ECM) deposition. Further, examination of Sirt7-depleted CFs demonstrated significantly lower expression of α-smooth muscle actin (α-SMA), the classical marker of MFs differentiation, and decreased formation of focal adhesions. Moreover, overexpression of Sirt7 increased α-SMA expression in Ang-II treated CFs and exacerbated Ang-II-induced MFs differentiation. Moreover, Sirt7 depletion could largely reverse Ang-II induced increase of nuclear translocalization and activity of smad2 and extracellular regulated kinases (ERK) in CFs. Importantly, the increased differentiation of CFs to MFs was also abolished by smad2 siRNA or U0126. Our findings reveal a novel role of Sirt7 and its phosphorylation in the phenotypic conversion of CFs to MFs and might lead to the development of new therapeutic and prognostic tools for cardiac fibrosis.


Assuntos
Angiotensina II/farmacologia , Fibroblastos/efeitos dos fármacos , Miofibroblastos/efeitos dos fármacos , Sirtuínas/genética , Proteína Smad2/genética , Actinas/genética , Actinas/metabolismo , Animais , Butadienos/farmacologia , Diferenciação Celular/efeitos dos fármacos , Proliferação de Células , Matriz Extracelular/efeitos dos fármacos , Matriz Extracelular/metabolismo , Fibroblastos/citologia , Fibroblastos/metabolismo , Adesões Focais/efeitos dos fármacos , Adesões Focais/metabolismo , Regulação da Expressão Gênica , Proteína Quinase 1 Ativada por Mitógeno/antagonistas & inibidores , Proteína Quinase 1 Ativada por Mitógeno/genética , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/antagonistas & inibidores , Proteína Quinase 3 Ativada por Mitógeno/genética , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Miocárdio/citologia , Miocárdio/metabolismo , Miofibroblastos/citologia , Miofibroblastos/metabolismo , Nitrilas/farmacologia , Fosforilação/efeitos dos fármacos , Inibidores de Proteínas Quinases/farmacologia , Transporte Proteico , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Ratos , Transdução de Sinais , Sirtuínas/antagonistas & inibidores , Sirtuínas/metabolismo , Proteína Smad2/agonistas , Proteína Smad2/metabolismo
15.
Cancer Discov ; 7(8): 852-867, 2017 08.
Artigo em Inglês | MEDLINE | ID: mdl-28408401

RESUMO

Effective therapies for non-small cell lung cancer (NSCLC) remain challenging despite an increasingly comprehensive understanding of somatically altered oncogenic pathways. It is now clear that therapeutic agents with potential to impact the tumor immune microenvironment potentiate immune-orchestrated therapeutic benefit. Herein, we evaluated the immunoregulatory properties of histone deacetylase (HDAC) and bromodomain inhibitors, two classes of drugs that modulate the epigenome, with a focus on key cell subsets that are engaged in an immune response. By evaluating human peripheral blood and NSCLC tumors, we show that the selective HDAC6 inhibitor ricolinostat promotes phenotypic changes that support enhanced T-cell activation and improved function of antigen-presenting cells. The bromodomain inhibitor JQ1 attenuated CD4+FOXP3+ T regulatory cell suppressive function and synergized with ricolinostat to facilitate immune-mediated tumor growth arrest, leading to prolonged survival of mice with lung adenocarcinomas. Collectively, our findings highlight the immunomodulatory effects of two epigenetic modifiers that, together, promote T cell-mediated antitumor immunity and demonstrate their therapeutic potential for treatment of NSCLC.Significance: Selective inhibition of HDACs and bromodomain proteins modulates tumor-associated immune cells in a manner that favors improved T-cell function and reduced inhibitory cellular mechanisms. These effects facilitated robust antitumor responses in tumor-bearing mice, demonstrating the therapeutic potential of combining these epigenetic modulators for the treatment of NSCLC. Cancer Discov; 7(8); 852-67. ©2017 AACR.This article is highlighted in the In This Issue feature, p. 783.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Inibidores de Histona Desacetilases/administração & dosagem , Ácidos Hidroxâmicos/administração & dosagem , Pirimidinas/administração & dosagem , Idoso , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Apoptose/efeitos dos fármacos , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/imunologia , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sinergismo Farmacológico , Feminino , Histona Desacetilases/genética , Histona Desacetilases/imunologia , Humanos , Ácidos Hidroxâmicos/efeitos adversos , Imunoterapia , Linfócitos do Interstício Tumoral/efeitos dos fármacos , Linfócitos do Interstício Tumoral/imunologia , Masculino , Camundongos , Pessoa de Meia-Idade , Pirimidinas/efeitos adversos , Ensaios Antitumorais Modelo de Xenoenxerto
16.
Theranostics ; 7(1): 67-80, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28042317

RESUMO

Cancer stem cells (CSCs) are considered one of the key contributors to chemoresistance and tumor recurrence. Therefore, the precise identification of reliable CSC markers and clarification of the intracellular signaling involved in CSCs remains a great challenge in fields relating to cancer biology. Here, we implemented a novel chemoresistant prostate cancer patient-derived xenograft (PDX) model in NOD/SCID mice and identified CD54 as a candidate gene among the most highly enriched gene expression profiles in prostate tumors exposed to chronic cisplatin administration. Additional in vitro and in vivo assays showed that CD54 played a critical role in the self-renewal and tumorigenesis of prostate CSCs. Moreover, silencing CD54 greatly reduced the tumorigenesis of prostate cancers both in vitro and in vivo and significantly extended the survival time of tumor-bearing mice in a prostate cancer xenograft model. Dissection of the molecular mechanism revealed that the p38-Notch1 axis was the main downstream signaling pathway in CD54-mediated regulation of CSCs in prostate cancers. Together, these results established that CD54 could be a novel reliable prostate CSC marker and provided a new potential therapeutic target in prostate cancer via CD54-Notch1 signaling.


Assuntos
Molécula 1 de Adesão Intercelular/metabolismo , Células-Tronco Neoplásicas/metabolismo , Neoplasias da Próstata/fisiopatologia , Receptor Notch1/metabolismo , Animais , Linhagem Celular Tumoral , Modelos Animais de Doenças , Perfilação da Expressão Gênica , Inativação Gênica , Xenoenxertos , Humanos , Masculino , Camundongos Endogâmicos NOD , Camundongos SCID , Análise de Sobrevida
17.
Methods Mol Biol ; 1404: 715-723, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27076332

RESUMO

Skin is a highly immunogenic site for vaccine delivery due to its richness of antigen-presenting cells. Several vaccines have been approved for skin delivery and in particular intradermal delivery in the last two decades. Yet intradermal delivery often causes frequent and severe local reactions, preventing the incorporation of adjuvants to further boost skin vaccination. Here we describe a novel skin delivery technology, called micro-fractional epidermal powder delivery or EPD, with minimized local reactions for improved skin vaccination. EPD is based on laser or microneedle treatment to generate microchannel arrays in the epidermis followed by topical application of powder vaccine-coated array patches to deliver vaccines into the skin via microchannels. Due to the fractional delivery, EPD significantly reduces vaccine/adjuvant-induced local reactions without compromising vaccine immunogenicity and adjuvant potency. EPD also eliminates needle injection-associated pain and is promising to improve vaccine stability due to the direct powder delivery. This chapter describes detailed methods for the advantageous EPD in preclinical animal models.


Assuntos
Microtecnologia/métodos , Pele , Vacinação/métodos , Animais , Anticorpos/análise , Anticorpos/imunologia , Ensaio de Imunoadsorção Enzimática , Camundongos , Microtecnologia/instrumentação , Pós , Vacinação/instrumentação
18.
Sci Rep ; 6: 22090, 2016 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-26915315

RESUMO

Hepatocellular carcinoma (HCC) and colorectal cancer (CRC) are among the most common cancers across the world. Particularly, a large number of patients with CRC also have liver metastasis. Currently, there are just a few targeted drugs against these two kinds of tumors which can only benefit a very small population of patients. Therefore, the need of more effective therapeutic drugs or strategies for these two types of cancers is urgent. PS341 (Bortezomib) is the first proteasome inhibitor drug which has been approved in clinical treatment for multiple myeloma. Here we demonstrated that PS341 negatively regulated HCC and CRC both in vitro and in vivo, including the inhibition of cell proliferation, epithelial-mesenchymal transition (EMT), the expression of stemness-related genes, cell migration and invasiveness. Mechanically, PS341 upregulated the expression of FOXO3, which inhibited the transcriptional activation of CTNNB1. The downregualtion of CTNNB1 led to apoptosis, cell cycle arrest, and the inhibition of migration, invasion, self-renewal and tumor formation of these two cancer types. In sum, our findings shed light on the PS341 mediated targeted therapy against both HCC and CRC in the future.


Assuntos
Bortezomib/farmacologia , Neoplasias Colorretais/tratamento farmacológico , Proteína Forkhead Box O3/efeitos dos fármacos , Neoplasias Hepáticas/tratamento farmacológico , Transdução de Sinais , beta Catenina/efeitos dos fármacos , Animais , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Camundongos , Invasividade Neoplásica
19.
Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi ; 30(11): 1184-9, 2014 Nov.
Artigo em Chinês | MEDLINE | ID: mdl-25374084

RESUMO

OBJECTIVE: To evaluate the change of regulatory T cells (Tregs) in patients with active systemic lupus erythematosus (SLE) using meta-analysis. METHODS: The PubMed and China Biomedical Literature (CBM) databases were searched for relevant studies up to August 31, 2013. After quality assessment and data extraction for included studies, a meta-analysis was performed using the software of Comprehensive-Meta Analysis (CMA) v2.2. RESULTS: Finally 22 case-control studies were recruited, including 12 studies reporting the change of Treg number and 12 studies for the change of Treg:CD4(+)T cell ratio. The quality of studies was moderate to high. It demonstrated that the Treg number in peripheral blood mononuclear cells (PBMCs) of active SLE patients significantly decreased than ones in controls (WMD=-1.23%, %CI=-1.87% to -0.59%). Then, subgroup analysis was performed based on the different surface markers of Tregs. It showed that the Treg number in PBMCs of active SLE patients decreased by 1.56% for the CD4(+)CD25(+) Tregs (WMD=-1.56%, 95% CI=-2.18% to -0.94%), and by 0.91% for the CD4(+)CD25(high) Tregs (WMD=-0.91%, 95% CI=-1.52% to -0.29%) compared with ones in controls. As for the ratio of Tregs to CD4(+) T cells, there was no significant difference between the SLE patients and the controls. Sensitivity analysis showed the results were robust, and the Funnel Plots showed there was no publication bias. CONCLUSION: Based on the current evidences, the development of SLE may be due to the decrease of Treg number in PBMCs, not to the abnormal ratio of Tregs to CD4(+) T cells.


Assuntos
Lúpus Eritematoso Sistêmico/imunologia , Linfócitos T Reguladores/imunologia , Humanos , Subunidade alfa de Receptor de Interleucina-2/imunologia
20.
PLoS One ; 9(8): e104426, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25099245

RESUMO

Human serum albumin (HSA) is extensively used in clinics to treat a variety of diseases, such as hypoproteinemia, hemorrhagic shock, serious burn injuries, cirrhotic ascites and fetal erythroblastosis. To address supply shortages and high safety risks from limited human donors, we recently developed recombinant technology to produce HSA from rice endosperm. To assess the risk potential of HSA derived from Oryza sativa (OsrHSA) before a First-in-human (FIH) trial, we compared OsrHSA and plasma-derived HSA (pHSA), evaluating the potential for an immune reaction and toxicity using human peripheral blood mononuclear cells (PBMCs). The results indicated that neither OsrHSA nor pHSA stimulated T cell proliferation at 1x and 5x dosages. We also found no significant differences in the profiles of the CD4(+) and CD8(+) T cell subsets between OsrHSA- and pHSA-treated cells. Furthermore, the results showed that there were no significant differences between OsrHSA and pHSA in the production of cytokines such as interferon-gamma (IFN-γ), tumor necrosis factor-alpha (TNF-α), interleukin (IL)-10 and IL-4. Our results demonstrated that OsrHSA has equivalent immunotoxicity to pHSA when using the PBMC model. Moreover, this ex vivo system could provide an alternative approach to predict potential risks in novel biopharmaceutical development.


Assuntos
Citocinas/metabolismo , Leucócitos Mononucleares/metabolismo , Oryza , Albumina Sérica/efeitos adversos , Albumina Sérica/farmacologia , Avaliação Pré-Clínica de Medicamentos , Humanos , Proteínas Recombinantes/efeitos adversos , Proteínas Recombinantes/farmacologia
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...