Overcoming erlotinib resistance with tailored treatment regimen in patient‐derived xenografts from naïve Asian NSCLC patients

Overall benefits of EGFR‐TKIs are limited because these treatments are largely only for adenocarcinoma (ADC) with EGFR activating mutation. The treatments also usually lead to development of resistances. We have established a panel of patient‐derived xenografts (PDXs) from treatment naïve Asian NSCLC patients, including those containing “classic” EGFR activating mutations. Some of these EGFR‐mutated PDXs do not respond to erlotinib: LU1868 containing L858R/T790M mutations, and LU0858 having L858R mutation as well as c‐MET gene amplification, both squamous cell carcinoma (SCC). Treatment of LU0858 with crizotinib, a small molecule inhibitor for ALK and c‐MET, inhibited tumor growth and c‐MET activity. Combination of erlotinib and crizotinib caused complete response, indicating the activation of both EGFR and c‐MET promote its growth/survival. LU2503 and LU1901, both with wild‐type EGFR and c‐MET gene amplification, showed complete response to crizotinib alone, suggesting that c‐MET gene amplification, not EGFR signaling, is the main oncogenic driver. Interestingly, LU1868 with the EGFR L858R/T790M, but without c‐met amplification, had a complete response to cetuximab. Our data offer novel practical approaches to overcome the two most common resistances to EGFR‐TKIs seen in the clinic using marketed target therapies. What's new? EGFR‐tyrosine kinase inhibitors (TKIs), erlotinib and gefitinib, are the two approved treatments for NSCLC adenocarcinoma (ADC) patients with activating EGFR mutations that occur more frequently in non‐smoking Asian female patients. However, drug resistance rapidly developed with two dominant genotypes: EGFR T790M “gatekeeper” mutation and c‐met gene amplification . Patient derived xenograft (PDX) mimics human cancers and has been reported to be predictive of drug effects in patients. The present study established a cohort of NSCLC, including non‐ADC PDX models of Asian origin containing EGFR mutations. Some of the models are found to be resistant to TKIs with classic mechanisms as seen in the clinics. We demonstrated that two existing target therapies could be tailored to overcome these resistances: 1) crizotinib, a c‐MET inhibitor, was effective in overcoming resistance caused by c‐met gene amplification, particularly when combined with erlotinib; 2) cetuximab, an EGFR inhibitor of distinct mechanism of action, was potent against EGFR T790M mutant. Our observation could therefore have important and practical implication treating EG