Co-occurring alterations in the RAS-MAPK pathway limit response to MET inhibitor treatment inMETexon 14 skipping mutation positive lung cancer

Abstract

Abstract:While patients with advanced-stage non-small cell lung cancers (NSCLCs) harboring MET exon 14 skipping mutations (METex14) often benefit from MET tyrosine kinase inhibitor (TKI) treatment, their long-term survival is limited by drug resistance. The molecular basis for this resistance remains incompletely understood. Through targeted sequencing analysis of cell-free circulating tumor DNA obtained from 289 patients with advanced-stage METex14 NSCLC, we find prominent co-occurring RAS pathway gene alterations (e.g. in KRAS/NRAS, NF1). Clinical resistance to MET TKI treatment was associated with the presence of these co-occurring alterations. In a new preclinical model expressing a METex14 mutation, KRAS overexpression promoted MET TKI resistance, which was overcome by co-treatment with crizotinib and the MEK inhibitor trametinib. Our study provides a genetic landscape of co-occurring alterations in advanced-stage METex14-mutated NSCLC and suggests a potential combination therapy strategy to enhance clinical outcomes. Statement of Significance:This report describes targeted sequencing of the largest reported cohort of advanced-stage NSCLC with a MET exon 14 skipping mutation. The data uncover certain RAS pathway genetic alterations as potential mediators of MEK TKI resistance, which could be overcome by MEK and MET co-inhibition in NSCLC.Introduction:

Histological characteristics of lung adenocarcinoma with uncommon actionable alterations: special emphasis on MET exon 14 skipping alterations

“…Recent studies showed that advanced‐stage NSCLCs often harboured multiple oncogenic alterations, which may impact its response to targeted therapies 7,31,32 . In METex14 , co‐occurring gene alterations in the phosphatidylinositol‐3‐kinase (PI3K) or RAS–mitogen‐activated protein kinase (RAS–MAPK) pathway have been shown in NSCLCs 33,34 . In the present cohort of surgically resected cases, concurrent METex14/PIK3CA mutations were detected in minimally invasive adenocarcinoma.…”

Downregulation of TMEM220 Promotes Tumor Progression in Hepatocellular Carcinoma

“…4a, b). C-MET (mesenchymal-epithelial transition factor/scatter factor receptor), which ligand is HGF/SF (ligand hepatocyte growth factor/scatter factor), can trigger various of downstream signaling pathways, such as PI3K/AKT, JAK/STAT, Ras/MAPK, and GSK3β/β-catenin [28][29][30]. The question arises as to how TMEM220 inhibits the activation of c-MET.…”

MET Exon 14 Skipping Alterations in Non-small Cell Lung Carcinoma—Current Understanding and Therapeutic Advances

“…and clinical data have demonstrated that tumors harboring METex14 skipping alterations along with other mutations, RAS-MAPK or PI3K/AKT pathway mutations, show reduced response to MET TKIs. [162][163][164] Overall, the resistance mechanisms against different types of MET inhibitor can be different. 109 Therapy combining relevant inhibitors can be helpful for the treatment of NSCLC with METex14 skipping alteration along with other driver mutations.…”

“…109 Therapy combining relevant inhibitors can be helpful for the treatment of NSCLC with METex14 skipping alteration along with other driver mutations. 164,165 Extensive studies are needed to unravel the full spectrum of resistance mechanisms against the inhibitor drugs for optimising therapeutic intervention.…”