RESUMO
MET is a receptor tyrosine kinase (RTK) responsible for initiating signaling pathways involved in development and wound repair. MET activation relies on ligand binding to the extracellular receptor, which prompts dimerization, intracellular phosphorylation, and recruitment of associated signaling proteins. Mutations, which are predominantly observed clinically in the intracellular juxtamembrane and kinase domains, can disrupt typical MET regulatory mechanisms. Understanding how juxtamembrane variants, such as exon 14 skipping (METΔEx14), and rare kinase domain mutations can increase signaling, often leading to cancer, remains a challenge. Here, we perform a parallel deep mutational scan (DMS) of the MET intracellular kinase domain in two fusion protein backgrounds: wild-type and METΔEx14. Our comparative approach has revealed a critical hydrophobic interaction between a juxtamembrane segment and the kinase âºC-helix, pointing to potential differences in regulatory mechanisms between MET and other RTKs. Additionally, we have uncovered a ß5 motif that acts as a structural pivot for the kinase domain in MET and other TAM family of kinases. We also describe a number of previously unknown activating mutations, aiding the effort to annotate driver, passenger, and drug resistance mutations in the MET kinase domain.
Assuntos
Proteínas Proto-Oncogênicas c-met , Proteínas Proto-Oncogênicas c-met/genética , Proteínas Proto-Oncogênicas c-met/metabolismo , Humanos , Domínios Proteicos/genética , Mutação , Motivos de Aminoácidos , Análise Mutacional de DNARESUMO
Lung cancer remains a formidable health challenge due to its high mortality and morbidity rates. Non-small cell lung cancer (NSCLC) constitutes approximately 85% of all lung cancer cases, with small cell lung cancer (SCLC) accounting for the remainder. Both NSCLC and SCLC cells express receptor tyrosine kinases, which may be overexpressed or mutated in lung cancer, leading to increased activation. The c-Met receptor tyrosine kinase, crucial for cell transformation and tumor growth, invasion, and metastasis, became the focus of our study. We used an E1B55KD-deleted, replication-selective oncolytic adenovirus (Ad.What), driven by the c-Met promoter, targeting lung cancer cells with c-Met overexpression, thus sparing normal cells. Previous studies have shown the enhanced antitumor efficacy of oncolytic adenoviruses when combined with chemotherapeutic agents. We explored combining rapamycin, a selective mTOR inhibitor with promising clinical trial outcomes for various cancers, with Ad.What. This combination increased infectivity by augmenting the expression of coxsackievirus and adenovirus receptors and αV integrin on cancer cells and induced autophagy. Our findings suggest that combining a c-Met promoter-driven oncolytic adenovirus with rapamycin could be an effective lung cancer treatment strategy, offering a targeted approach to exploit lung cancer cells' vulnerabilities, potentially marking a significant advancement in managing this deadly disease.
Assuntos
Adenoviridae , Neoplasias Pulmonares , Terapia Viral Oncolítica , Vírus Oncolíticos , Regiões Promotoras Genéticas , Proteínas Proto-Oncogênicas c-met , Sirolimo , Humanos , Proteínas Proto-Oncogênicas c-met/metabolismo , Proteínas Proto-Oncogênicas c-met/genética , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/terapia , Neoplasias Pulmonares/patologia , Regiões Promotoras Genéticas/genética , Adenoviridae/genética , Linhagem Celular Tumoral , Terapia Viral Oncolítica/métodos , Vírus Oncolíticos/genética , Sirolimo/farmacologia , Sirolimo/uso terapêutico , Animais , Camundongos , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/terapia , Carcinoma Pulmonar de Células não Pequenas/patologiaRESUMO
Non-small cell lung cancer (NSCLC) remains a significant challenge, as it is one of the leading causes of cancer-related deaths, and the development of resistance to anticancer therapy makes it difficult to treat. In this study, we investigated the anticancer mechanism of deoxybouvardin (DB), a cyclic hexapeptide, in gefitinib (GEF)-sensitive and -resistant NSCLC HCC827 cells. DB inhibited the viability and growth of HCC827 cells in a concentration- and time-dependent manner. In vitro kinase assay showed DB inhibited epidermal growth factor receptor (EGFR), mesenchymal-epithelial transition (MET), and AKT, and their phosphorylation was suppressed in HCC827 cells treated with DB. A molecular docking model suggested that DB interacts with these kinases in the ATP-binding pockets. DB induces ROS generation and cell cycle arrest. DB treatment of HCC827 cells leads to mitochondrial membrane depolarization. The induction of apoptosis through caspase activation was confirmed by Z-VAD-FMK treatment. Taken together, DB inhibited the growth of both GEF-sensitive and GEF-resistant NSCLC cells by targeting EGFR, MET, and AKT and inducing ROS generation and caspase activation. Further studies on DB can improve the treatment of chemotherapy-resistant NSCLC through the development of effective DB-based anticancer agents.
Assuntos
Apoptose , Carcinoma Pulmonar de Células não Pequenas , Receptores ErbB , Neoplasias Pulmonares , Proteínas Proto-Oncogênicas c-akt , Proteínas Proto-Oncogênicas c-met , Transdução de Sinais , Humanos , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Receptores ErbB/metabolismo , Gefitinibe/farmacologia , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Simulação de Acoplamento Molecular , Peptídeos Cíclicos/farmacologia , Fosforilação/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Proto-Oncogênicas c-met/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacosRESUMO
A novel group of indolyl-1,2,4-triazole-chalcone hybrids was designed, synthesized, and assessed for their anticancer activity. The synthesized compounds exhibited significant antiproliferative activity. Compounds 9a and 9e exhibited significant cancer inhibition with GI50 ranging from 3.69 to 20.40 µM and from 0.29 to >100 µM, respectively. Both compounds displayed a broad spectrum of anticancer activity with selectivity ratios ranging between 0.50-2.78 and 0.25-2.81 at the GI50 level, respectively. The synthesized compounds were also screened for their cytotoxicity by 3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyltetrazol (MTT) assay and for inhibition of epidermal growth factor receptor (EGFR) and c-MET (mesenchymal-epithelial transition factor). Some of the tested compounds exhibited significant inhibition against EGFR and/or c-MET. Compound 9b showed the highest c-MET inhibition (IC50 = 4.70 nM) compared to foretinib (IC50 = 2.5 nM). Compound 9d showed equipotent activity compared with erlotinib against EGFR (IC50 = 0.052 µM) and displayed significant c-MET inhibition with an IC50 value of 4.90 nM.
Assuntos
Antineoplásicos , Proliferação de Células , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Receptores ErbB , Indóis , Inibidores de Proteínas Quinases , Proteínas Proto-Oncogênicas c-met , Triazóis , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/metabolismo , Humanos , Proteínas Proto-Oncogênicas c-met/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-met/metabolismo , Antineoplásicos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Relação Estrutura-Atividade , Proliferação de Células/efeitos dos fármacos , Triazóis/farmacologia , Triazóis/química , Triazóis/síntese química , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Indóis/farmacologia , Indóis/química , Indóis/síntese química , Relação Dose-Resposta a Droga , Estrutura Molecular , Linhagem Celular Tumoral , Chalconas/farmacologia , Chalconas/síntese química , Chalconas/química , Chalcona/farmacologia , Chalcona/química , Chalcona/síntese químicaRESUMO
Cigarette smoke, a complex mixture produced by tobacco combustion, contains a variety of carcinogens and can trigger DNA damage. Overactivation of c-MET, a receptor tyrosine kinase, may cause cancer and cellular DNA damage, but the underlying mechanisms are unknown. In this work, we investigated the mechanisms of cigarette smoke extract (CSE) induced malignant transformation and DNA damage in human bronchial epithelial cells (BEAS-2B). The results demonstrated that CSE treatment led to up-regulated mRNA expression of genes associated with the c-MET signaling pathway, increased expression of the DNA damage sensor protein γ-H2AX, and uncontrolled proliferation in BEAS-2B cells. ATR, ATR, and CHK2, which are involved in DNA damage repair, as well as the phosphorylation of c-MET and a group of kinases (ATM, ATR, CHK1, CHK2) involved in the DNA damage response were all activated by CSE. In addition, CSE activation promotes the phosphorylation modification of ATR, CHK1 proteins associated with DNA damage repair. The addition of PHA665752, a specific inhibitor of c-MET, or knock-down with c-MET both attenuated DNA damage, while overexpression of c-MET exacerbated DNA damage. Thus, c-MET phosphorylation may be involved in CSE-induced DNA damage, providing a potential target for intervention in the prevention and treatment of smoking-induced lung diseases.
Assuntos
Brônquios , Dano ao DNA , Células Epiteliais , Nicotiana , Proteínas Proto-Oncogênicas c-met , Fumaça , Humanos , Proteínas Proto-Oncogênicas c-met/metabolismo , Fosforilação/efeitos dos fármacos , Células Epiteliais/efeitos dos fármacos , Brônquios/efeitos dos fármacos , Brônquios/citologia , Fumaça/efeitos adversos , Transformação Celular Neoplásica/efeitos dos fármacos , Transformação Celular Neoplásica/induzido quimicamente , Linhagem Celular , Transdução de Sinais/efeitos dos fármacos , Produtos do TabacoRESUMO
BACKGROUND: Pancreatic adenocarcinoma (PAAD), known for its high lethality, has not been thoroughly explored in terms of its mechanisms and patterns of immune infiltration. Disulfidptosis, a newly identified mode of cell death, is likely associated with tumorigenesis and progression but remains poorly understood in PAAD at the genetic and mechanistic levels. METHODS: Sixteen PAAD samples from the GSE154778 scRNA-seq dataset were subjected to single-cell analysis. Disulfidptosis grouping and scores were established across various immune cell populations. Using the TCGA-PAAD database, LASSO regression was employed to construct prognostic markers linked to disulfidptosis. The performance of this model was assessed in both training and independent validation cohorts. Subsequent analyses explored the correlations between disulfidptosis scores, immune infiltration, and drug sensitivity. Cellular experiments further confirmed the significant positive relationship of the gene MET with disulfidptosis and its role in influencing the invasion and metastasis of PAAD. RESULTS: WGCNA identified Disulf-High and Disulf-Low as modules strongly correlated with disulfidptosis. Five prognostically significant genes were selected to construct prognostic models. Survival analysis demonstrated that the disulfidptosis-related biological model successfully achieved prognostic stratification in PAAD patients. Additionally, the disulfidptosis score was significantly correlated with both immune infiltration and drug sensitivity. Knockdown of the MET gene substantially inhibited cell multiplication and cell cycle progression in two PAAD cell lines, effects potentially induced by the activation of the PI3K/AKT signalling pathway in the tumour. CONCLUSION: Key genes associated with disulfidptosis significantly correlate with immune infiltration and the development of PAAD. Biomarkers based on disulfidptosis present potential avenues for novel therapies and clinical treatments in PAAD.
Assuntos
Adenocarcinoma , Biomarcadores Tumorais , Aprendizado de Máquina , Neoplasias Pancreáticas , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patologia , Neoplasias Pancreáticas/metabolismo , Humanos , Biomarcadores Tumorais/metabolismo , Biomarcadores Tumorais/genética , Prognóstico , Adenocarcinoma/genética , Adenocarcinoma/patologia , Adenocarcinoma/metabolismo , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica , Proteínas Proto-Oncogênicas c-met/metabolismo , Proteínas Proto-Oncogênicas c-met/genética , ApoptoseRESUMO
Traditionally, the D1228 E/G/H/N mutation has been thought to cause Type I MET-TKI resistance. We reported a 75-year-old female with non-small cell lung cancer harboring MET exon 14 skipping mutation, who developed acquired MET D1228H mutation induced by capmatinib treatment. Interestingly, the patient demonstrated marked response to second-line savolitinib treatment with the duration of response of 19 months and several additional metastatic lesions appeared. Pathological assessment of rebiopsy sample showed adenocarcinoma and targeted next-generation sequencing revealed the loss of MET D1228H mutation and presence of MET p.Y1230N mutation. In response, the treatment regimen was amended to include a daily administration of 60 mg of cabozantinib, which resulted in moderate size reduction of the tumours. The switch of resistance mutations indicated that different type Ib MET inhibitors may exhibit distinct mechanisms of resistance. We call for futher studies on resistance based on patient-derived pre-clinical models including patient-derived tumor-like cell clusters, patient-derived organoids, and patient-derived xenografts.
Assuntos
Adenocarcinoma de Pulmão , Resistencia a Medicamentos Antineoplásicos , Éxons , Neoplasias Pulmonares , Mutação , Proteínas Proto-Oncogênicas c-met , Humanos , Proteínas Proto-Oncogênicas c-met/genética , Feminino , Idoso , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Resistencia a Medicamentos Antineoplásicos/genética , Adenocarcinoma de Pulmão/tratamento farmacológico , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/patologia , Benzamidas , Acrilamidas/uso terapêutico , Triazinas/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Inibidores de Proteínas Quinases/farmacologia , Piridinas/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Imidazóis , PirazinasRESUMO
BACKGROUND: We evaluated the efficacy and safety of tepotinib in patients with various solid cancers harboring MET exon 14 skipping mutation (METex14) or MET gene amplification. PATIENTS AND METHODS: A phase II, multicenter study was conducted in patients with advanced or metastatic solid cancers who progressed after standard treatment, harboring either METex14 or MET amplification detected in tissue-based next-generation sequencing (NGS). The primary endpoint was objective response rate (ORR). For exploratory analyses, we analyzed the gene profiles using plasma NGS test. RESULTS: Thirty-five patients were enrolled. The ORR was 57.6% for all patients, 52.2% for those with METex14, and 70% for those with MET amplification. Median progression-free survival (PFS) was 8 months [95% confidence interval (CI) 4.5-11.5 months] and median overall survival (OS) was 14 months (95% CI 7.8-20.2 months) in all patients. For patients with non-small-cell lung cancer with METex14, the median PFS was 9 months (95% CI 4.7-13.4 months) and the median OS was 17 months [95% CI not applicable (NA)-NA]. For patients with MET amplification, the median PFS was 7 months (95% CI 1.5-12.5 months) and the median OS was 10 months (95% CI 5.8-14.2 months). The ORR of patients with MET dysregulation detected by plasma NGS was 72.2%, whereas the ORR was 30% in those without detection. The most common adverse events were peripheral edema, asthenia, transaminase elevation, and anorexia, mostly grade 1 or 2. CONCLUSIONS: Tepotinib demonstrated consistent antitumor activity in patients with METex14, and promising antitumor activity in various cancers with MET amplification. Detection of MET dysregulation by plasma NGS may predict the response to tepotinib.
Assuntos
Éxons , Amplificação de Genes , Mutação , Neoplasias , Proteínas Proto-Oncogênicas c-met , Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Proteínas Proto-Oncogênicas c-met/genética , Idoso , Neoplasias/tratamento farmacológico , Neoplasias/genética , Adulto , Éxons/genética , Pirimidinas/uso terapêutico , Pirimidinas/farmacologia , Idoso de 80 Anos ou mais , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Piperidinas , PiridazinasRESUMO
c-MET and STAT-3 are significant targets for cancer treatments. Here, we describe a class of very effective dual STAT-3 and c-MET inhibitors with coumarin-based thiazoles (3a-o) as its scaffold. Spectroscopic evidence (NMR, HRMS, and HPLC) validated the structural discoveries of the new compounds. The cytotoxic activity of these compounds was also tested against a panel of cancer cells in accordance with US-NCI guidelines. Compound 3g proved to be active at 10 µM, thus it was automatically scheduled to be tested at five doses. Towards SNB-75 (CNS cancer cell line), compound 3g showed notable in vitro anti-cancer activity with GI50 = 1.43 µM. For the molecular targets, compound 3g displayed potent activity towards STAT-3 and c-MET having IC50 of 4.7 µM and 12.67, respectively, compared to Cabozantinib (IC50 = 15 nM of c-MET) and STAT-3-IN-3 (IC50 = 2.1 µM of STAT-3). Moreover, compound 3g significantly induced apoptosis in SNB-75 cells, causing a 3.04-fold increase in apoptotic cell death (treated cells exhibited 11.53 % overall apoptosis, against 3.04 % in reference cells) and a 3.58-fold increase in necrosis. Moreover, it arrests cells at the G2 phase. Dual inhibition of c-MET and STAT-3 protein kinase was further validated using RT-PCR. The target compound's binding mechanism was determined by the application of molecular docking.
Assuntos
Antineoplásicos , Proliferação de Células , Cumarínicos , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Proteínas Proto-Oncogênicas c-met , Fator de Transcrição STAT3 , Tiazóis , Humanos , Cumarínicos/farmacologia , Cumarínicos/química , Cumarínicos/síntese química , Proteínas Proto-Oncogênicas c-met/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-met/metabolismo , Fator de Transcrição STAT3/antagonistas & inibidores , Fator de Transcrição STAT3/metabolismo , Antineoplásicos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Tiazóis/farmacologia , Tiazóis/química , Tiazóis/síntese química , Relação Estrutura-Atividade , Estrutura Molecular , Proliferação de Células/efeitos dos fármacos , Linhagem Celular Tumoral , Apoptose/efeitos dos fármacos , Relação Dose-Resposta a Droga , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Simulação de Acoplamento MolecularRESUMO
Non-small cell lung cancer (NSCLC) is characterized by several molecular alterations that contribute to its development and progression. These alterations include the epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), human epidermal growth factor receptor 2 (HER2), and mesenchymal-epithelial transition factor (c-MET). Among these, the hepatocyte growth factor (HGF)/c-MET signaling pathway plays a crucial role in NSCLC. In spite of this, the involvement of the HGF/c-MET signaling axis in remodeling the tumor microenvironment (TME) remains relatively unexplored. This review explores the biological functions of the HGF/c-MET signaling pathway in both normal and cancerous cells, examining its multifaceted roles in the NSCLC tumor microenvironment, including tumor cell proliferation, migration and invasion, angiogenesis, and immune evasion. Furthermore, we summarize the current progress and clinical applications of MET-targeted therapies in NSCLC and discuss future research directions, such as the development of novel MET inhibitors and the potential of combination immunotherapy.
Assuntos
Carcinoma Pulmonar de Células não Pequenas , Fator de Crescimento de Hepatócito , Neoplasias Pulmonares , Proteínas Proto-Oncogênicas c-met , Transdução de Sinais , Microambiente Tumoral , Humanos , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Proteínas Proto-Oncogênicas c-met/metabolismo , Fator de Crescimento de Hepatócito/metabolismo , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , AnimaisRESUMO
Mesenchymal-epithelial transition factor (MET) is a receptor tyrosine kinase that serves a critical function in numerous developmental, morphogenic, and proliferative signaling pathways. If dysregulated, MET has been shown to be involved in the development and survival of several cancers, including non-small cell lung cancer (NSCLC), renal cancer, and other epithelial tumors. Currently, the clinical efficacy of FDA approved MET inhibitors is limited by on-target acquired resistance, dose-limiting toxicities, and less than optimal efficacy against brain metastasis. Therefore, there is still an unmet medical need for the development of MET inhibitors to address these issues. Herein we report the application of structure-based design for the discovery and development of a novel class of brain-penetrant MET inhibitors with enhanced activity against clinically relevant mutations and improved selectivity. Compound 13 with a MET D1228N cell line IC50 value of 23 nM showed good efficacy in an intracranial tumor model and increased the median overall survival of the animals to 100% when dosed orally at 100 mg/kg daily for 21 days.
Assuntos
Antineoplásicos , Inibidores de Proteínas Quinases , Proteínas Proto-Oncogênicas c-met , Pirazóis , Proteínas Proto-Oncogênicas c-met/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-met/metabolismo , Humanos , Animais , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/uso terapêutico , Pirazóis/farmacologia , Pirazóis/química , Pirazóis/síntese química , Linhagem Celular Tumoral , Relação Estrutura-Atividade , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Antineoplásicos/uso terapêutico , Descoberta de Drogas , Pirazinas/farmacologia , Pirazinas/síntese química , Pirazinas/química , Pirazinas/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/patologia , Camundongos , Mutação , RatosRESUMO
The combination of BRAF and MEK inhibitors demonstrated significant clinical benefit in patients with BRAF-mutant non-small cell lung cancer (NSCLC). However, the molecular mechanisms of acquired resistance to BRAF and MEK inhibition in NSCLC are still unknown. Herein, we report a case of a 76-year-old man with a history of smoking who was diagnosed with BRAF V600E-mutant lung adenocarcinoma (PD-L1â >â 50%) and subsequently candidate to first-line therapy with pembrolizumab. After 18â months since the start of immunotherapy, computed tomography scan showed disease progression and a second-line therapy with dabrafenib and trametinib was initiated. Seven months later, due to a suspect disease progression, a left supraclavicular lymphadenectomy was performed and next-generation sequencing analysis revealed the appearance of MET exon 14 skipping mutation, while fluorescence in situ hybridization analysis showed MET amplification. The patient is still on BRAF and MEK inhibitor treatment. Our case highlights the relevance of performing tumor tissue rebiopsy at the time of progression during treatment with BRAF/MEK inhibition with the aim of identifying putative mechanisms of resistance.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Carcinoma Pulmonar de Células não Pequenas , Resistencia a Medicamentos Antineoplásicos , Imidazóis , Neoplasias Pulmonares , Mutação , Oximas , Proteínas Proto-Oncogênicas B-raf , Proteínas Proto-Oncogênicas c-met , Piridonas , Pirimidinonas , Humanos , Piridonas/administração & dosagem , Pirimidinonas/administração & dosagem , Masculino , Oximas/administração & dosagem , Idoso , Proteínas Proto-Oncogênicas B-raf/genética , Imidazóis/administração & dosagem , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Proteínas Proto-Oncogênicas c-met/genética , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêuticoRESUMO
BACKGROUND: Limited data exists on the efficacy of immune checkpoint inhibitor (ICI) combinations in non-small-cell lung cancer (NSCLC) with uncommon driver alterations in genes such as ERBB2, BRAF, RET, and MET. This study retrospectively assessed ICI-combination therapy outcomes in this molecular subset of NSCLC. METHODS: We retrospectively analyzed patients with advanced NSCLC confirmed with driver alterations in genes including ERBB2, BRAF, RET or MET, and received ICI combined with chemotherapy (ICI + chemo) and/or targeted therapy (ICI + chemo/TT) as first-line (1L) or second- or third-line (≥ 2L) treatment at Hunan Cancer Hospital between January 2018 and May 2024. RESULTS: Of the 181 patients included in the study, 131 patients received 1L-ICI + chemo (ERBB2, n = 64; BRAF, n = 34; RET, n = 23; and MET, n = 10), and 50 patients received ≥ 2L-ICI + chemo/TT (ERBB2, n = 16; BRAF, n = 7; RET, n = 14; MET, n = 13). The full cohort had an overall response rate (ORR) of 45.9% and disease control rate of 84.0%. Among patients who received 1L-ICI + chemo, ORR ranged between 51.6% and 60.0%, with the median progression-free survival (mPFS) and overall survival (mOS) of 8.2 and 21.0 months for those with ERBB2-altered tumors, 10.0 and 15.0 months for BRAF-altered tumors, 12.1 months and OS not reached for RET-altered tumors, and 6.2 and 28.0 months for MET-altered tumors, respectively. Additionally, ORR ranged between 14.3% and 30.8% for ≥ 2L-ICI + chemo/TT; mPFS and mOS were 5.4 and 16.2 months for patients with ERBB2-altered tumors, 2.7 and 5.0 months for BRAF-altered tumors, 6.2 and 14.3 months for RET-altered tumors, and 5.7 and 11.5 months for MET-altered tumors, respectively. CONCLUSION: ICI-based combination therapies, regardless of treatment line, were effective in treating patients with advanced NSCLC harboring driver alterations in ERBB2, BRAF, RET, or MET. This suggests their potential as alternative treatment options in this patient population.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Carcinoma Pulmonar de Células não Pequenas , Inibidores de Checkpoint Imunológico , Neoplasias Pulmonares , Receptor ErbB-2 , Humanos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Carcinoma Pulmonar de Células não Pequenas/patologia , Inibidores de Checkpoint Imunológico/uso terapêutico , Masculino , Feminino , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Pessoa de Meia-Idade , Idoso , Estudos Retrospectivos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Adulto , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismo , Idoso de 80 Anos ou mais , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas c-ret/genética , Resultado do Tratamento , Mutação , Proteínas Proto-Oncogênicas c-met/genéticaRESUMO
BACKGROUND: Patients with EGFR-mutated non-small-cell lung cancer (NSCLC) and MET amplification as a mechanism of resistance to first-line osimertinib have few treatment options. Here, we report the primary analysis of the phase 2 INSIGHT 2 study evaluating tepotinib, a highly selective MET inhibitor, combined with osimertinib in this population. METHODS: This open-label, phase 2 study was conducted at 179 academic centres and community clinics in 17 countries. Eligible patients were aged 18 years or older with an Eastern Cooperative Oncology Group performance status of 0 or 1 and advanced or metastatic EGFR-mutated NSCLC of any histology, with MET amplification by tissue biopsy fluorescence in-situ hybridisation (FISH; MET gene copy number of ≥5 or MET-to-CEP7 ratio of ≥2) or liquid biopsy next-generation sequencing (MET plasma gene copy number of ≥2·3), following progression on first-line osimertinib. Patients received oral tepotinib 500 mg plus oral osimertinib 80 mg once daily. The primary endpoint was independently assessed objective response in patients with MET amplification by central FISH treated with tepotinib plus osimertinib with at least 9 months of follow-up. Safety was analysed in patients who received at least one study drug dose. This study is registered with ClinicalTrials.gov, NCT03940703 (enrolment complete). FINDINGS: Between Feb 13, 2020, and Nov 4, 2022, 128 patients (74 [58%] female, 54 [42%] male) were enrolled and initiated tepotinib plus osimertinib. The primary activity analysis population included 98 patients with MET amplification confirmed by central FISH, previous first-line osimertinib and at least 9 months of follow-up (median 12·7 months [IQR 9·9-20·3]). The confirmed objective response rate was 50·0% (95% CI 39·7-60·3; 49 of 98 patients). The most common treatment-related grade 3 or worse adverse events were peripheral oedema (six [5%] of 128 patients), decreased appetite (five [4%]), prolonged electrocardiogram QT interval (five [4%]), and pneumonitis (four [3%]). Serious treatment-related adverse events were reported in 16 (13%) patients. Deaths of four (3%) patients were assessed as potentially related to either trial drug by the investigator due to pneumonitis (two [2%] patients), decreased platelet count (one [1%]), respiratory failure (one [1%]), and dyspnoea (one [1%]); one death was attributed to both pneumonitis and dyspnoea. INTERPRETATION: Tepotinib plus osimertinib showed promising activity and acceptable safety in patients with EGFR-mutated NSCLC and MET amplification as a mechanism of resistance to first-line osimertinib, suggesting a potential chemotherapy-sparing oral targeted therapy option that should be further investigated. FUNDING: Merck (CrossRef Funder ID: 10.13039/100009945).
Assuntos
Acrilamidas , Compostos de Anilina , Protocolos de Quimioterapia Combinada Antineoplásica , Carcinoma Pulmonar de Células não Pequenas , Receptores ErbB , Amplificação de Genes , Neoplasias Pulmonares , Mutação , Proteínas Proto-Oncogênicas c-met , Humanos , Acrilamidas/uso terapêutico , Feminino , Masculino , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Proteínas Proto-Oncogênicas c-met/genética , Pessoa de Meia-Idade , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Idoso , Receptores ErbB/genética , Receptores ErbB/antagonistas & inibidores , Compostos de Anilina/uso terapêutico , Compostos de Anilina/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Adulto , Pirimidinas/efeitos adversos , Pirimidinas/uso terapêutico , Pirimidinas/administração & dosagem , Progressão da Doença , Idoso de 80 Anos ou mais , Indóis , Piperidinas , PiridazinasRESUMO
Objective To explore the potential of the cell surface receptor c-Met as an effective target for chimeric antigen receptor T-cell (CAR-T) therapy in colorectal cancer. Methods The bioinformatics was used to analyze the specific expression of c-Met in colorectal adenocarcinoma (COAD) and its clinical significance. c-Met protein expression was detected by immunohistochemistry in tumor tissues obtained from colorectal cancer patients. Flow cytometry was utilized to assess the expression of c-Met in the HCT116 human colorectal cancer cell line. Additionally, primary T cells isolated from human peripheral blood mononuclear cells (PBMCs) were transduced with a lentivirus to generate second-generation CAR-T cells targeting c-Met, followed by an observation of the inhibitory effects of these c-Met-targeted CAR-T cells on HCT116 cells. Results Immunohistochemistry and bioinformatics data both demonstrated that c-Met was over-expressed in COAD, with patients exhibiting relatively lower expression showing better prognosis. In normal colonic tissue, c-Met was either expressed at low levels or not expressed. Flow cytometry revealed high expression of c-Met in HCT116 cells as well. The c-Met-targeted CAR-T cells were capable of specifically recognizing and targeting antigen-expressing tumor cells. CAR-T cells proliferated specifically under antigenic stimulation, exerting cytotoxic effects on cancer cells and releasing cytokines interleukin 2 (IL-2) and interferon-gamma (IFN-γ), thereby demonstrating the biological functions. Conclusion c-Met may be a promising therapeutic target in COAD; c-Met-targeted CAR-T cells demonstrate inhibitory effects on colorectal cancer cells in vitro.
Assuntos
Neoplasias Colorretais , Biologia Computacional , Proteínas Proto-Oncogênicas c-met , Receptores de Antígenos Quiméricos , Humanos , Neoplasias Colorretais/terapia , Neoplasias Colorretais/imunologia , Neoplasias Colorretais/genética , Proteínas Proto-Oncogênicas c-met/metabolismo , Proteínas Proto-Oncogênicas c-met/genética , Proteínas Proto-Oncogênicas c-met/imunologia , Receptores de Antígenos Quiméricos/imunologia , Receptores de Antígenos Quiméricos/genética , Células HCT116 , Transição Epitelial-Mesenquimal , Imunoterapia Adotiva/métodos , Linhagem Celular Tumoral , Linfócitos T/imunologia , Linfócitos T/metabolismoRESUMO
BACKGROUND: Mesenchymal-epithelial transition (MET) exon 14 (METex14) skipping mutation is a rare alteration in non-small-cell lung cancer (NSCLC), occurring in about 3%-4% of cases. Here we report disease and patient characteristics, and efficacy and tolerability of MET inhibitors among advanced METex14 NSCLC patients from the Italian real-world registry ATLAS. MATERIALS AND METHODS: Clinical-pathological and molecular data, and treatment efficacy/tolerability outcomes were retrospectively collected from the ATLAS registry. RESULTS: From July 2020 to July 2023 a total of 146 METex14 advanced NSCLC patients were included across 27 Italian centers. Median age was 74 years, and most patients were male (52%), with an Eastern Cooperative Oncology Group performance status < 2 (72%) and adenocarcinoma subtype (83%). One hundred and twenty-five out of 146 (86%) patients received at least one line of systemic anticancer therapy. Fifty-six (38%) were treated with capmatinib and 34 (23%) with tepotinib. 29% and 52% of them received targeted treatment in the first and second line, respectively. In the cohort of patients treated with MET inhibitors, the response rate (RR) was 37% (33% in previously treated patients and 46% in treatment-naïve) with a disease control rate of 62%. With a median follow-up of 10.8 months, progression-free survival was 6.6 months [95% confidence interval (CI) 4.3-8.3 months] and overall survival was 10.7 months (95% CI 7.2-19.3 months). In patients with measurable brain metastases (17 cases), the intracranial RR was 41%. Grade ≥3 treatment-related adverse events (TRAEs) occurred in 12% of patients with grade 3 peripheral edema in 7% of cases. A fatal adverse reaction occurred in one patient due to pneumonitis. TRAEs-related dose reduction and discontinuation were reported in 6% and 8% of cases, respectively. CONCLUSION: Capmatinib and tepotinib represent an effective treatment option in NSCLC patients with METex14. Real-world efficacy outcomes are worse than those reported in prospective clinical trials. Their activity is more pronounced in the treatment-naïve population, suggesting that this is the right setting in the management of patients with METex14.
Assuntos
Carcinoma Pulmonar de Células não Pequenas , Éxons , Neoplasias Pulmonares , Mutação , Proteínas Proto-Oncogênicas c-met , Humanos , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/patologia , Masculino , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Proteínas Proto-Oncogênicas c-met/genética , Feminino , Idoso , Itália , Estudos Retrospectivos , Pessoa de Meia-Idade , Benzamidas/uso terapêutico , Benzamidas/farmacologia , Idoso de 80 Anos ou mais , Triazinas/uso terapêutico , Triazinas/farmacologia , Piridinas/uso terapêutico , Piridinas/farmacologia , Piridazinas/uso terapêutico , Piridazinas/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Inibidores de Proteínas Quinases/farmacologia , Imidazóis , Piperidinas , PirimidinasAssuntos
Carcinoma Pulmonar de Células não Pequenas , Éxons , Neoplasias Pulmonares , Proteínas Proto-Oncogênicas c-met , Pirimidinas , Diálise Renal , Humanos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/complicações , Carcinoma Pulmonar de Células não Pequenas/patologia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/complicações , Proteínas Proto-Oncogênicas c-met/genética , Éxons/genética , Pirimidinas/uso terapêutico , Masculino , Insuficiência Renal/terapia , Piridinas/uso terapêutico , Pessoa de Meia-Idade , Idoso , Antineoplásicos/uso terapêutico , Piperidinas , PiridazinasRESUMO
Emerging therapies for non-small cell lung cancer targeting c-Met overexpression have recently demonstrated promising results. However, the evaluation of c-Met expression can be challenging. We aimed to study the inter and intraobserver reproducibility of c-Met expression evaluation. One hundred ten cases with non-small cell lung cancer (40 biopsies and 70 surgical specimens) were retrospectively selected in a single laboratory (LPCE) and evaluated for c-Met expression. Six pathologists (4 seniors and 2 juniors) evaluated the H-score and made a 3-tier classification of c-Met expression for all cases, using conventional light microscopy (CLM) and whole slide imaging (WSI). The interobserver reproducibility with CLM gave global Cohen Kappa coefficients (Æ) ranging from 0.581 (95% CI: 0.364-0.771) to 0.763 (95% CI: 0.58-0.92) using the c-Met 3-tier classification and H-score, respectively. Æ was higher for senior pathologists and biopsy samples. The interobserver reproducibility with WSI gave a global Æ ranging from 0.543 (95% CI: 0.33-0.724) to 0.905 (95% CI: 0.618-1) using the c-Met H-score and 2-tier classification (≥25% 3+), respectively. Æ for intraobserver reproducibility between CLM and WSI ranged from 0.713 to 0.898 for the c-Met H-score and from 0.600 to 0.779 for the c-Met 3-tier classification. We demonstrated a moderate to excellent interobserver agreement for c-Met expression with a substantial to excellent intraobserver agreement between CLM and WSI, thereby supporting the development of digital pathology. However, some factors (scoring method, type of tissue samples, and expertise level) affect reproducibility. Our findings highlight the importance of establishing a consensus definition and providing further training, particularly for inexperienced pathologists, for c-Met immunohistochemistry assessment in clinical practice.
Assuntos
Biomarcadores Tumorais , Carcinoma Pulmonar de Células não Pequenas , Imuno-Histoquímica , Neoplasias Pulmonares , Microscopia , Variações Dependentes do Observador , Proteínas Proto-Oncogênicas c-met , Humanos , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma Pulmonar de Células não Pequenas/química , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Proteínas Proto-Oncogênicas c-met/análise , Proteínas Proto-Oncogênicas c-met/metabolismo , Reprodutibilidade dos Testes , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/química , Biomarcadores Tumorais/análise , Estudos Retrospectivos , Masculino , Feminino , Valor Preditivo dos Testes , Biópsia , IdosoAssuntos
Bexaroteno , Proteínas Proto-Oncogênicas c-ret , Humanos , Bexaroteno/uso terapêutico , Bexaroteno/farmacologia , Proteínas Proto-Oncogênicas c-ret/genética , Pirazóis/uso terapêutico , Mielofibrose Primária/tratamento farmacológico , Mielofibrose Primária/genética , Antineoplásicos/uso terapêutico , Tetra-Hidronaftalenos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Mutação , Piridinas/uso terapêutico , Proteínas Proto-Oncogênicas c-met/genética , Aprovação de Drogas , Leucemia-Linfoma de Células T do Adulto/tratamento farmacológico , Leucemia-Linfoma de Células T do Adulto/genética , Leucemia-Linfoma de Células T do Adulto/patologia , Pirimidinas/uso terapêutico , Morfolinas/uso terapêutico , Tiazóis/uso terapêutico , Tiazóis/farmacologia , Éxons , BenzamidasRESUMO
OBJECTIVES: Comprehensive data using Next-Generation Sequence (NGS) and fluorescence in situ hybridization (FISH) for detecting MET amplification is limited in Chinese patients, we evaluating NGS performance both in tissue and plasma samples using FISH as reference. We also sought to find optimal thresholds value for NGS in detecting MET amplification via bioinformatics methods. METHOD: Patients progressed after 1st-, 2nd-, or 3rd-generation (G) EGFR-TKIs were enrolled. Tissue biopsy samples were performed for MET amplification detection via both NGS and FISH. Paired plasma samples were collected for MET amplification detection by NGS. The sensitivity, specificity and agreement were analyzed between NGS and FISH. RESULTS: 116 eligible patients were analyzed. 44 patients were male. 82 patients were after 3rd generation EGFR-TKI. MET amplification was detected in 43 (37.1 %) patients by FISH, including 19 (16.4 %) polysomy and 24 (20.7 %) focal amplification. The positive rate of MET amplification in post 3rd generation EGFR-TKI and post 1st/2ndgeneration EGFR-TKI resistant patients was 42.7 % (35/82), and 23.5 % (8/34). The sensitivity, specificity and agreement of detecting MET amplification by NGS in tissue were 39.5 % (17/43), 98.6 % (72/73) and 76.7 % (89/116), respectively, 66.7 % (16/24), 98.6 % (72/73) and 90.7 % (88/97) for focal MET amplification in tissue and 29.2 % (7/24), 94.5 % (69/73), 78.4 % (76/97) for focal amplification in plasma. Results were shown in the table below. CONCLUSION: NGS is an alternative method for MET focal amplification detection in tissue. While the sensitivity of NGS testing in plasma needs further improvement to maximize identification of patients with potential benefit from dual-targeted therapy.