ERBB2 and MET alterations include both activating mutations and gene amplifications, detection of which relies on molecular methods with a minimal role for IHC in NSCLC.
ALK and ROS1 are prognostic and predictive tumor markers in non-small cell lung carcinoma (NSCLC), which are more often found in lung adenocarcinomas as with other oncogenes such as EGFR, KRAS, or C-MET.
The clinical resistance of non-small cell lung cancer (NSCLC) to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) has been linked to EGFR T790M resistance mutations or MET amplifications.
These results demonstrated how the mutated residues tune the crizotinib response and may assist kinase inhibitor development especially for ALK G1202R, analogous to the ROS1 G2302R and METG1163R mutations that are also resistant to crizotinib treatment in NSCLC.
Non-small cell lung cancer (NSCLC) sensitive to first-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) often acquires resistance through secondary EGFR mutations, including the T790M mutation, aberrant c-Met receptor activity, or both.
<i>ROS1</i> rearrangements define a distinct molecular subset of non-small-cell lung cancer (NSCLC), which can be treated effectively with crizotinib, a tyrosine kinase inhibitor (TKI) targeting <i>ROS1/MET/ALK</i> rearrangements.
We analyzed MET gene copy number using FISH in two related NSCLC cell lines, one sensitive (HCC827) and one resistant (HCC827 GR6) to gefitinib therapy and in two different NSCLC patient populations: 24 never smokers or EGFR FISH-positive patients treated with gefitinib (ONCOBELL cohort) and 182 surgically resected NSCLC not exposed to anti-EGFR agents.
Sustained activation, overexpression, or mutation of the MET pathway is associated with a poor prognosis in a variety of tumors, including non-small cell lung cancer (NSCLC), implicating the MET pathway as a potential therapeutic target for lung cancer.
Although epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) have been introduced for the treatment of non-small cell lung cancer (NSCLC), the emergence of secondary T790M mutation in EGFR or amplification of the Met proto-oncogene restrain the clinical success of EGFR-TKIs.
Resected NSCLC were assessed for MET gene copy number (GCN) and expression using silver in-situ hybridization (SISH) and immunohistochemistry (IHC) on TMAs in a multicenter setting.
Most non-small cell lung cancer (NSCLC) tumors with activating mutations of the epidermal growth factor receptor (EGFR) are initially responsive to first-generation, reversible EGFR tyrosine kinase inhibitors (TKI) such as gefitinib, but they subsequently develop resistance to these drugs through either acquisition of an additional T790M mutation of EGFR or amplification of the proto-oncogene MET.
Using patient-derived cell line and xenografts, we characterize the mechanism of crizotinib resistance mediated by <i>KRAS</i> amplification in <i>MET</i>ex14-mutant NSCLC and demonstrate the superior efficacy of the dual MET/PI3K inhibition as a therapeutic strategy addressing this resistance mechanism.
Clinically, EGFR-positive NSCLC acquires several resistance mechanisms during EGFR-TKI treatment, such as the emergence of a secondary mutation (T790M), MET gene amplification, and transformation to small cell lung cancer.
Multiregion single-nucleotide polymorphism array analysis was performed on 13 early-stage resected EGFR-mutant-positive NSCLC across 59 sectors to investigate intratumoral heterogeneity of MET CNG.