Combined treatment with MET inhibitors and other therapies in lung cancer.
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ABSTRACT:
SUBMITTER: Bagai R
PROVIDER: S-EPMC4367561 | biostudies-literature | 2012 Sep
REPOSITORIES: biostudies-literature
Publications
Combined treatment with MET inhibitors and other therapies in lung cancer.
Bagai Rakesh R Ma Patrick C PC
Translational lung cancer research 20120901 3
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Project description:MET and its ligand hepatocyte growth factor/scatter factor (HGF) influence cell motility and lead to tumor growth, invasion, and angiogenesis. Alterations in MET have been observed in non-small cell lung cancer (NSCLC) tumors, with increased expression associated with more aggressive cancer, as well as acquired resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI). MET inhibitors act via two basic mechanisms. Small molecule inhibitors antagonize ATP in the intracellular tyrosine kinase domain of MET, with studies on the following agents reviewed here: tivantinib (ARQ-197), cabozantinib (XL-184), crizotinib (PF-02341066), amuvatinib (MP470), MGCD265, foretinib (EXEL-2880), MK2461, SGX523, PHA665752, JNJ-38877605, SU11274, and K252A. The monoclonal monovalent antibody fragment onartuzumab (MetMAb) is also discussed here, which binds to and prevents the extracellular activation of the receptor by ligand. MET inhibition may both overcome the negative prognostic effect of MET tumor expression as well as antagonize MET-dependent acquired resistance to EGFR inhibitors. Here we discuss MET inhibitors in combination with other therapies in lung cancer.
| S-EPMC4367550 | biostudies-literature
Project description:BackgroundDysregulation of the mesenchymal epithelial transition (MET) pathway contributes to poor clinical outcomes in patients with non-small cell lung cancer (NSCLC). Numerous clinical trials are currently investigating several therapies based on modulation of the MET pathway.ObjectivesThis study aimed to systematically evaluate the activity and safety of MET inhibitors in patients with NSCLC.MethodsWe searched PubMed, Embase, and the Cochrane Library from inception to June 02, 2022. The objective response rate (ORR) and disease control rate (DCR) were extracted as the main outcomes and pooled using the weighted mean proportion with fixed- or random-effects models in cases of significant heterogeneity (I 2>50%). Safety analysis was performed based on adverse events reported in all studies.ResultsEleven studies (882 patients) were included in the meta-analysis. The pooled ORR was 28.1% (95% confidence interval [CI], 0.223-0.354), while the pooled DCR was 69.1% (95% CI, 0.631-0.756). ORRs were higher for tepotinib (44.7% [95% CI, 0.365-0.530]) and savolitinib (42.9% [95% CI, 0.311-0.553]) than for other types of MET inhibitors. Patients with NSCLC with exon 14 skipping exhibited higher ORRs (39.3% (95% CI, 0.296-0.522)) and DCRs (77.8% (95% CI, 0.714-0.847)) than those with MET protein overexpression or amplification. Intracranial response rate and intracranial disease control rates were 40.1% (95% CI, 0.289-0.556) and 95.4% (95% CI, 0.892-0.100), respectively. Adverse events were mild (grade 1 to 2) in 87.2% of patients. Common adverse events above grade 3 included lower extremity edema (3.5% [95% CI, 0.027-0.044]), alanine aminotransferase (ALT) elevation (2.4% [95% CI, 0.014-0.033]), and lipase elevation (2.2% [95% CI, 0.016-0.031]).ConclusionMET inhibitors, which exhibited a satisfactory safety profile in the current study, may become a new standard of care for addressing MET dysregulation in patients with advanced or metastatic NSCLC, and even in those with brain metastases, particularly tepotinib, savolitinib and capmatinib. Further randomized trials are required to establish standard predictive biomarkers for MET therapies and to compare the effects of different MET inhibitors in NSCLC with MET dysregulation.
| S-EPMC9646943 | biostudies-literature
Project description:IntroductionAlterations in the MET gene, including amplifications and exon 14 skipping mutations, have been identified as actionable oncogenic alterations. However, MET fusions are rarely detected in lung cancer, and their sensitivity to therapeutics has not been systematically analyzed.MethodsThe data from 30876 lung cancer patients from the LAVA database and 7966 patients from cBioPortal database were screened. Basic demographic and clinical information for the patients harboring MET fusions were collected. A lung squamous cell cancer patient harboring a novel EML4-MET fusion was treated with crizotinib. Additionally, a literature review was performed to summarize the cases of patients harboring MET fusions and their treatment information.ResultsMET fusions were found in only 0.2% to 0.3% of lung cancer patients and appeared in almost all exons of the MET gene. Intragenic MET fusions were found in 52.6% (41/78) of the included patients. Crizotinib was effective for MET fusions, including a novel identified EML4-MET fusion, even after the failure of multiple lines of treatment. This result suggested that acquired MET fusions become more regionally selective, as they usually occurred in exons encoding the extracellular region. Interestingly, the MET-fused genes in primary MET fusions or acquired MET fusions were very different, which indicated the different functions and influences of the disease.ConclusionMET fusions are rare, and half of the fusion types were intragenic fusions. Lung cancer patients harboring primary or acquired MET fusions could benefit from crizotinib. In addition, EML4-MET was first reported in this study as a novel MET fusion type.
| S-EPMC9960416 | biostudies-literature
Project description:Treatment of non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) activating mutation with EGFR-TKIs has achieved great success, yet faces the development of acquired resistance as the major obstacle to long-term disease remission in the clinic. MET (or c-MET) gene amplification has long been known as an important resistance mechanism to first- or second-generation EGFR-TKIs in addition to the appearance of T790 M mutation. Recent preclinical and clinical studies have suggested that MET amplification and/or protein hyperactivation is likely to be a key mechanism underlying acquired resistance to third-generation EGFR-TKIs such as osimertinib as well, particularly when used as a first-line therapy. EGFR-mutant NSCLCs that have relapsed from first-generation EGFR-TKI treatment and have MET amplification and/or protein hyperactivation should be insensitive to osimertinib monotherapy. Therefore, combinatorial therapy with osimertinib and a MET or even a MEK inhibitor should be considered for these patients with resistant NSCLC carrying MET amplification and/or protein hyperactivation.
| S-EPMC6588884 | biostudies-literature
Project description:Receptor tyrosine kinases play important roles in the biology of many tumor cell types. In approximately 10% of non-small cell lung cancer (NSCLC) patients mutational activation of the epidermal growth factor receptor (EGFR) results in tumor cells that are exquisitely addicted to signaling by this receptor. (1) Thus expression of mutant active EGFR but in general not wild-type EGFR predisposes NSCLC cells to inhibitors of EGFR/ErbB2. Use of EGFR inhibitory agents such as gefitinib for this subset of NSCLC patients causes tumor regression and disease stabilization for 12-18 mo, after which tumor cells become resistant to the drug. (2) Initial studies identified a second mutation within the EGFR, which results in the resistance of the tyrosine kinase to gefitinib, as a major cause of reduced tumor control. (3) This has resulted in the development of newer EGFR inhibitors, e.g., afatinib, which inhibited double mutant EGFR. (4) In a subset of these patients, however, resistance to gefitinib was not associated with EGFR mutations. (5) Clearly, other mechanisms of gefitinib resistance must be at play.
| S-EPMC4049779 | biostudies-other
Project description:Small cell lung cancer (SCLC) is the most aggressive type of lung cancer. The different systemic treatment approaches attempted in the last 35 years have not improved overall survival in the advanced stage. Targeted therapies assessed in clinical trials have failed to show efficacy against SCLC. Within the potentially interesting targets, the hepatocyte growth factor (HGF)/mesenchymal-epithelial transition (MET) pathway activation is associated with worse survival and chemoresistance in SCLC. Preclinical data suggest that the inhibition of the MET pathway can revert chemoresistance and prevent tumor growth. Recently, immunotherapy has shown modest but relevant activity in SCLC. Interestingly, MET modulation seems to be involved in increasing the efficacy of standard checkpoint inhibitors. Here, we review the preclinical and clinical data of MET inhibition in SCLC, and the role of this pathway in the immune response.
| S-EPMC6827355 | biostudies-literature
Project description:Genomic MET amplification and exon 14 skipping are currently clinically recognized biomarkers for stratifying subsets of non-small cell lung cancer (NSCLC) patients according to the predicted response to c-Met inhibitors (c-Metis), yet the overall clinical benefit of this strategy is quite limited. Notably, c-Met protein overexpression, which occurs in approximately 20-25% of NSCLC patients, has not yet been clearly defined as a clinically useful biomarker. An optimized strategy for accurately classifying patients with c-Met overexpression for decision-making regarding c-Meti treatment is lacking. Herein, we found that SYK regulates the plasticity of cells in an epithelial state and is associated with their sensitivity to c-Metis both in vitro and in vivo in PDX models with c-Met overexpression regardless of MET gene status. Furthermore, TGF-β1 treatment resulted in SYK transcriptional downregulation, increased Sp1-mediated transcription of FRA1, and restored the mesenchymal state, which conferred resistance to c-Metis. Clinically, a subpopulation of NSCLC patients with c-Met overexpression coupled with SYK overexpression exhibited a high response rate of 73.3% and longer progression-free survival with c-Meti treatment than other patients. SYK negativity coupled with TGF-β1 positivity conferred de novo and acquired resistance. In summary, SYK regulates cell plasticity toward a therapy-sensitive epithelial cell state. Furthermore, our findings showed that SYK overexpression can aid in precisely stratifying NSCLC patients with c-Met overexpression regardless of MET alterations and expand the population predicted to benefit from c-Met-targeted therapy.
| S-EPMC10183461 | biostudies-literature
Project description:Although surgical resection and liver transplantation are the only treatment modalities that enable prolonged survival in patients with hepatocellular carcinoma (HCC), the majority of HCC patients presents with advanced disease and do not undergo resective or ablative therapy. Transarterial chemoembolization (TACE) is indicated in intermediate/advanced stage unresectable HCC even in the setting of portal vein involvement (excluding main portal vein). Sorafenib has been shown to improve survival of patients with advanced HCC in two controlled randomized trials. Yttrium 90 is a safe microembolization treatment that can be used as an alternative to TACE in patients with advanced liver only disease or in case of portal vein thrombosis. External beam radiation can be helpful to provide local control in selected unresectable HCC. These different treatment modalities may be combined in the treatment strategy of HCC and also used as a bridge to resection or liver transplantation. Patients should undergo formal multidisciplinary evaluation prior to initiating any such treatment in order to individualize the best available options.
| S-EPMC2951818 | biostudies-other
Project description:BACKGROUND:Interstitial lung disease (ILD) is a group of diffuse lung diseases that mainly involve the interstitial and alveolar cavities and result in loss of alveolar-capillary functional units, leading to restrictive ventilatory dysfunction and diffusion impairment. There was an increased incidence of lung cancer on the basis of ILD, and perioperative risk of patients with lung cancer combined with ILD (LC-ILD) was significantly increased. The aim of this study is to summarize the safety and experience of surgical treatment of LC-ILD. METHODS:A retrospective analysis was performed on 23 patients with LC-ILD who underwent pneumonectomy in Beijing Hospital from January 2012 to December 2019, and their clinical manifestations, image feature, pathology, surgical safety, perioperative complications and treatment experience were summarized. RESULTS:A total of 23 patients were included in this study, including 20 males (87.0%) with an average age of (69.1±7.8) years, and 19 cases (82.6%) were smokers. Of the ILD types, 14 cases (60.9%) were idiopathic pulmonary fibrosis, 7 cases (30.4%) were idiopathic nonspecific interstitial pneumonia, and 2 (8.7%) were interstitial lung disease associated with connective tissue diseases. The pathology of lung cancer included adenocarcinoma (30.4%, 7/23), small cell carcinoma (30.4%, 7/23), squamous cell carcinoma (26.1%, 6/23), small cell carcinoma mixed with squamous cell carcinoma (4.3%, 1/23) and large cell neuroendocrine carcinoma (8.7%, 2/23). Surgical approaches included video assisted thoracoscopy (69.6%, 16/23) and anterolateral thoracotomy (30.4%, 7/23), with lobectomy (52.2%, 12/23), double lobectomy (4.3%, 1/23), and sublobectomy (39.1%, 9/23). There were 11 cases (47.8%) of postoperative complications, including 8 cases (34.8%) of pulmonary complications, 4 cases (17.4%) of acute exacerbation of ILD (AE-ILD), 6 cases (26.1%) of atrial fibrillation, and 1 case (4.3%) of acute left ventricular dysfunction. The 90-day mortality is 8.7% (2/23) and the cause of death was acute exacerbation of ILD. CONCLUSIONS:Most of LC-ILD were elderly patients with multiple comorbidities and decreased pulmonary function, leading to significantly increased surgical risk. The ILD should be fully evaluated and controlled before surgery, intraoperative trauma should be minimized, and special attention should be paid to pulmonary complications and AE-ILD after surgery. Postoperative AE-ILD has a poor prognosis and glucocorticoids may be effective. Early diagnosis and treatment is the key to treatment of AE-ILD.
| S-EPMC7260382 | biostudies-literature
Project description:Treatment of advanced non-small cell lung cancer (NSCLC) has radically improved in the last years due to development and clinical approval of highly effective agents including immune checkpoint inhibitors (ICIs) and oncogene-directed therapies. Molecular profiling of lung cancer samples for activated oncogenes, including epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), c-ros oncogene 1 (ROS1) and BRAF, is routinely performed to select the most appropriate up-front treatment. However, the identification of new therapeutic targets remains a high priority. Recently, MET exon 14 skipping mutations have emerged as novel actionable oncogenic alterations in NSCLC, sensitive to MET inhibition. In this review we discuss: (I) MET gene and MET receptor structure and signaling pathway; (II) MET exon 14 alterations; (III) current data on MET inhibitors, mainly focusing on selective MET tyrosine kinase inhibitors (TKIs), in the treatment of NSCLC with MET exon 14 skipping mutations. We identified the references for this review through a literature search of papers about MET, MET exon 14 skipping mutations, and MET inhibitors, published up to September 2020, by using PubMed, Scopus and Web of Science databases. We also searched on websites of main international cancer congresses (ASCO, ESMO, IASLC) for ongoing studies presented as abstracts. MET exon 14 skipping mutations have been associated with clinical activity of selective MET inhibitors, including capmatinib, that has recently received approval by FDA for clinical use in this subgroup of NSCLC patients. A large number of trials are testing MET inhibitors, also in combinatorial therapeutic strategies, in MET exon 14-altered NSCLC. Results from these trials are eagerly awaited to definitively establish the role and setting for use of these agents in NSCLC patients.
| S-EPMC8044480 | biostudies-literature