MET Exon 14 Alterations in Lung Cancer: Exon Skipping Extends Half-Life.
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ABSTRACT:
SUBMITTER: Drilon A
PROVIDER: S-EPMC4911276 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundNon-small cell lung cancers (NSCLCs) harboring specific genetic alterations can be highly sensitive to targeted therapies.Materials and methodsWe performed a targeted rearrangement assay on 54 NSCLCs across all stages that were from patients who were never smokers and did not have driver mutations. Because MET exon 14 skipping was the most frequent alteration found, we surveyed the results for MET exon 14 skipping at Massachusetts General Hospital (MGH) since the inclusion of this alteration into our current molecular profiling panel.ResultsIn a cohort of 54 never-smokers with lung cancers that were wild-type for known driver mutations, MET exon 14 skipping was the most frequently recurring alteration, occurring in 10 cancers (19%). Clinical testing at MGH via our next-generation sequencing (NGS) and NGS-rearrangement panels showed an additional 16 cases of MET exon 14 skipping, for an overall estimated frequency of 5.6%. A clinical case of a patient with MET exon 14 skipping treated with the MET inhibitor crizotinib is also described.ConclusionMET exon 14 skipping is a targetable gene alteration found in NSCLC. Patients with these alterations may respond well to MET inhibition.Implications for practiceMET exon 14 skipping occurs with an approximately 5% frequency in NSCLC and is seen in both squamous and adenocarcinoma histology. Patients whose cancers have MET exon 14 skipping can respond well to MET inhibitors. Molecular testing for MET exon 14 skipping should be performed on all lung cancers because this is a targetable alteration.
| S-EPMC4828128 | biostudies-literature
Project description:Recently, targeted therapy has achieved great success in the treatment of non-small cell lung cancer (NSCLC) patients. Mesenchymal to epithelial transition factor (MET) is considered to be another important molecular target for NSCLC since epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK). Accumulating clinical trials and case reports have confirmed that MET inhibitors exhibited a potential prospect in treating patients with MET 14 exon skipping alterations, suggesting that MET 14 exon skipping mutation might be an effective biomarker for MET inhibitors, which remains to be confirmed by more clinical data. This review summarizes current research about the molecular mechanism, clinicopathological characterization, treatment strategies and drug resistance mechanisms of MET 14 exon skipping alterations in NSCLC.?.
| S-EPMC6058657 | biostudies-literature
Project description:It has been over three decades since the hepatocyte growth factor (HGF) ligand and its receptor MET proto-oncogene (MET) pathway was established as promoting cancer growth and metastasis. MET exon 14 skipping (METex14) alterations occur in 3-4% of all non-small cell lung cancer (NSCLC) patients, typically in elderly patients (older than 70 years), and result in constitutive activation of the MET receptor by altering a region required for receptor degradation. Multi-kinase inhibitor of MET, such as crizotinib, and more recently selective MET inhibitors, such as capmatinib and tepotinib, have demonstrated clinical efficacy and safety in METex14 NSCLC patients in clinical trials. These results have led to the approval of MET inhibitors by regulatory agencies across the globe. The success also fueled the excitement of further development of therapeutic strategies to target METex14 in lung cancers. This article provides an overview of the clinical development program targeting METex14 in NSCLC, including small molecular tyrosine kinase inhibitors and anti-MET antibodies. Furthermore, combination therapy immune checkpoint inhibitors or other targeted therapies are also under development in various patient populations, with acquired resistance immune or targeted therapy. Clinical trials in different development stages are ongoing and more drugs targeted to c-MET will be available for NSCLC patients with METex14 skipping mutations in the future.
| S-EPMC7890719 | biostudies-literature
Project description:Somatic mutations of MET gene are emerging as important driver mutations for lung cancers. To identify the common clinicopathological features of MET exon 14 skipping mutations and amplification and clarify whether the two MET gene alterations cause protein overexpression were investigated using 196 lung cancer samples of Taiwan through real time-qPCR/sequencing, fluorescence in situ hybridization, and immunohistochemistry. The two MET gene alterations are both present in low frequency, ~1%, in the studied lung cancer population of Taiwan. MET exon 14 skipping mutations were identified from two early-stage patients, who were both relatively advanced in age, and did not carry other driver mutations. One was an adenocarcinoma and the other was a rare carcinosarcoma. Three gene amplifications cases were identified. Neither of the two MET gene alterations would lead to protein overexpression; hence, direct detection in nucleic acid level would be a preferred and straightforward solution for the identification of skipping mutations. The presence of MET exon 14 mutations in minor histological types of lung cancers urge to extend screening scope of this mutation in lung cancer and treatment response evaluation in clinical trials. These would be important next steps for the success of MET target therapy in clinical practice.
| S-EPMC6675391 | biostudies-literature
Project description:PurposeAlthough patients with advanced-stage non-small cell lung cancers (NSCLC) harboring MET exon 14 skipping mutations (METex14) often benefit from MET tyrosine kinase inhibitor (TKI) treatment, clinical benefit is limited by primary and acquired drug resistance. The molecular basis for this resistance remains incompletely understood.Experimental designTargeted sequencing analysis was performed on cell-free circulating tumor DNA obtained from 289 patients with advanced-stage METex14-mutated NSCLC.ResultsProminent co-occurring RAS-MAPK pathway gene alterations (e.g., in KRAS, NF1) were detected in NSCLCs with METex14 skipping alterations as compared with EGFR-mutated NSCLCs. There was an association between decreased MET TKI treatment response and RAS-MAPK pathway co-occurring alterations. In a preclinical model expressing a canonical METex14 mutation, KRAS overexpression or NF1 downregulation hyperactivated MAPK signaling to promote MET TKI resistance. This resistance was overcome by cotreatment with crizotinib and the MEK inhibitor trametinib.ConclusionsOur study provides a genomic landscape of co-occurring alterations in advanced-stage METex14-mutated NSCLC and suggests a potential combination therapy strategy targeting MAPK pathway signaling to enhance clinical outcomes.
| S-EPMC6980768 | biostudies-literature
Project description:MET exon 14 skipping alterations (METex14) comprise a diverse set of actionable oncogene drivers in non-small-cell lung cancer (NSCLC). Recent studies have established the efficacy of tyrosine kinase inhibitors for this patient population. The landscape of co-occurring genetic alterations in METex14 NSCLC and their potential impact to therapeutic sensitivities has not yet been fully described. METex14 NSCLC cases were collected from three cohorts: the VISION trial, and data sets from Guardant360 and GenePlus. Clinicopathologic characteristics and METex14 mutation sites were analyzed and compared across data sets. Co-occurring genetic alterations and the clonality relationships to METex14 were evaluated. Of 40,824 NSCLCs, 692 METex14 cases (1.7%) were identified, including 332 in Guardant360, 188 in VISION, and 172 in GenePlus. The demographics and mutation type and/or sites were similar in the Asian versus Western cohorts. MET amplification, which were found to be associated with sensitivity to MET kinase inhibitors, co-occurs in 7.6%-13.8% of cases, whereas kinase domain secondary mutation of MET co-occurs in 5%-6%. When co-occurring with METex14, EGFR mutations were often identified as the dominant clone (78%, 7 of 9), whereas when co-occurring, METex14 (39%, 7 of 18) and KRAS (44%, 8 of 18) had similar rates of clonal dominance. PIK3CA and PTEN mutations were almost always subclones (89%, 16 of 18) to METex14. Moreover, RET-CCDC6 fusion and EGFR mutation were detected following crizotinib treatment in two patients, suggesting novel mechanisms of resistance. METex14 mutations frequently co-occur with other potential driver oncogenes with differing patterns of clonal dominance observed among the drivers. This cellular context can provide insights into whether METex14 is acting as a primary oncogenic driver or resistance mechanism and help guide treatment choices.
| S-EPMC8694524 | biostudies-literature
Project description:BackgroundA splice-site mutation that results in a loss of transcription of exon 14 in the oncogenic driver MET occurs in 3 to 4% of patients with non-small-cell lung cancer (NSCLC). We evaluated the efficacy and safety of tepotinib, a highly selective MET inhibitor, in this patient population.MethodsIn this open-label, phase 2 study, we administered tepotinib (at a dose of 500 mg) once daily in patients with advanced or metastatic NSCLC with a confirmed MET exon 14 skipping mutation. The primary end point was the objective response by independent review among patients who had undergone at least 9 months of follow-up. The response was also analyzed according to whether the presence of a MET exon 14 skipping mutation was detected on liquid biopsy or tissue biopsy.ResultsAs of January 1, 2020, a total of 152 patients had received tepotinib, and 99 patients had been followed for at least 9 months. The response rate by independent review was 46% (95% confidence interval [CI], 36 to 57), with a median duration of response of 11.1 months (95% CI, 7.2 to could not be estimated) in the combined-biopsy group. The response rate was 48% (95% CI, 36 to 61) among 66 patients in the liquid-biopsy group and 50% (95% CI, 37 to 63) among 60 patients in the tissue-biopsy group; 27 patients had positive results according to both methods. The investigator-assessed response rate was 56% (95% CI, 45 to 66) and was similar regardless of the previous therapy received for advanced or metastatic disease. Adverse events of grade 3 or higher that were considered by investigators to be related to tepotinib therapy were reported in 28% of the patients, including peripheral edema in 7%. Adverse events led to permanent discontinuation of tepotinib in 11% of the patients. A molecular response, as measured in circulating free DNA, was observed in 67% of the patients with matched liquid-biopsy samples at baseline and during treatment.ConclusionsAmong patients with advanced NSCLC with a confirmed MET exon 14 skipping mutation, the use of tepotinib was associated with a partial response in approximately half the patients. Peripheral edema was the main toxic effect of grade 3 or higher. (Funded by Merck [Darmstadt, Germany]; VISION ClinicalTrials.gov number, NCT02864992.).
| S-EPMC8422679 | biostudies-literature
Project description:Savolitinib is a tyrosine kinase inhibitor being developed for the treatment of metastatic non-small cell lung cancer (NSCLC) with mesenchymal-epithelial transition (MET) factor exon 14 skipping alterations. However, the role of savolitinib in neoadjuvant therapy for lung cancer remains unclear. Here, we present a case of a 65-year-old woman diagnosed with stage IIIA (cT2bN2M0, eighth TNM stage) upper right lung adenocarcinoma harboring MET exon 14 skipping alterations. After 4 weeks of therapy, a partial response was achieved with neoadjuvant savolitinib, and significant shrinkage in tumor and lymph nodes was observed. We also measured the immune microenvironment of the primary tumor pre- and posttreatment with savolitinib.
| S-EPMC9514319 | biostudies-literature
Project description:MET exon 14 (METex14) skipping mutations are an emerging potentially targetable oncogenic driver mutation in non-small-cell lung cancer (NSCLC). The imaging features and patterns of metastasis of NSCLC with primary METex14 skipping mutations (METex14-mutated NSCLC) are not well described. Our goal was to determine the clinicopathologic and imaging features that may suggest the presence of METex14 skipping mutations in NSCLC. This IRB-approved retrospective study included NSCLC patients with primary METex14 skipping mutations and pre-treatment imaging data between January 2013 and December 2018. The clinicopathologic characteristics were extracted from electronic medical records. The imaging features of the primary tumor and metastases were analyzed by two thoracic radiologists. In total, 84 patients with METex14-mutated NSCLC (mean age = 71.4 ± 10 years; F = 52, 61.9%, M = 32, 38.1%; smokers = 47, 56.0%, nonsmokers = 37, 44.0%) were included in the study. Most tumors were adenocarcinoma (72; 85.7%) and presented as masses (53/84; 63.1%) that were peripheral in location (62/84; 73.8%). More than one in five cancers were multifocal (19/84; 22.6%). Most patients with metastatic disease had only extrathoracic metastases (23/34; 67.6%). Fewer patients had both extrathoracic and intrathoracic metastases (10/34; 29.4%), and one patient had only intrathoracic metastases (1/34, 2.9%). The most common metastatic sites were the bones (14/34; 41.2%), the brain (7/34; 20.6%), and the adrenal glands (7/34; 20.6%). Four of the 34 patients (11.8%) had metastases only at a single site. METex14-mutated NSCLC has distinct clinicopathologic and radiologic features.
| S-EPMC6966679 | biostudies-literature
Project description:Several oncogenic mechanisms have been identified for MET, including MET amplification, fusions, mutations in the tyrosine kinase domain and exon 14 skipping alterations. MET exon 14 mutations are found in about 3-5% of non-small-cell lung cancers. Dysregulation of the MET receptor leads to cell proliferation and survival by activation of the PI3K-AKT-TOR and RAS-RAF-MET-ERK canonical pathways. Targeting the MET tyrosine kinase domain in the setting of MET exon 14 mutations using effective MET tyrosine kinase inhibitors is a current targeted therapy option for patients with metastatic lung cancer. In this Review, we focus on the management of patients with MET exon 14 skipping alterations by addressing the biology of the MET receptor and exon 14 skipping mutations, current treatment strategies, and sequential treatment options based on resistance mechanisms to MET inhibitors in patients with non-small-cell lung cancer.
| S-EPMC9255265 | biostudies-literature