Abstract
MET overexpression and the EGFR T790M mutation are both associated with acquired resistance (AR) to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) in advanced non-small cell lung cancer (NSCLC). We characterized the frequency, underlying molecular mechanisms, and subsequent treatment for AR in MET overexpressing NSCLC patients with or without the T790M mutation. The study participants were 207 patients with advanced NSCLC and AR to EGFR-TKIs. The percentages of MET-, T790M- and MET/T790M-positive patients were 20.3% (42/207), 34.8% (72/207) and 6.8% (14/207), respectively. The disease control rate was 100% (5/5) for five patients with MET overexpression who received EGFR-TKIs plus a MET inhibitor. Among the MET/T790M-positive patients, seven received EGFR-TKIs plus a MET inhibitor and four received a T790M inhibitor, but no response was observed. The median post-progression survival (PPS) was 14.1, 24.5, and 10.7 months for MET-overexpressing, T790M-positive and MET/T790M-positive patients, respectively (P=0.044). c-Met, p-Met, ERBB3, and p-ERBB3 were highly expressed in MET-positive and MET/T790M-positive patients, but were poorly expressed in T790M-positive patients. EGFR, p-EGFR, AKT, p-AKT, MAPK, and p-MAPK were highly expressed in all three groups. These results suggest that MET/T790M-positive patients are at higher risk of AR to EGFR-TKIs, and have a worse PPS than patients with only MET overexpression or the T790M mutation alone. Clinical trials are needed to determine the best treatment for patients with both MET overexpression and the EGFR T790M mutation.
Highlights
Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), gefitinib, erlotinib, and afatinib,are effective therapeutic agents against nonsmall cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR)-activating mutations, such as the exon 19 deletion and the L858R point mutation [1]
These results suggest that MET/T790M-positive patients are at higher risk of acquired resistance (AR) to EGFR-TKIs, and have a worse post-progression survival (PPS) than patients with only MET overexpression or the T790M mutation alone
From January 2013 to October 2015, 207 advanced non-small cell lung cancer (NSCLC) patients with AR to gefitinib or erlotinib were prospectively enrolled in the study (Table S1)
Summary
Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), gefitinib, erlotinib, and afatinib,are effective therapeutic agents against nonsmall cell lung cancer (NSCLC) with EGFR-activating mutations, such as the exon 19 deletion and the L858R point mutation [1]. Studies reported that tumors with MET 14 exon skipping responded well to crizotinib [9,10,11,12,13]. It has been suggested that a combination of the epidermal growth factor receptor (EGFR) and a MET inhibitor might be effective for overcoming resistance to EGFRTKIs in NSCLC [3, 17]. This study combined gefitinib and INC280, and was used to treat EGFR mutant patients with AR in combination with MET amplification or MET overexpression [18]
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