Integrative Genomic Analysis of Drug Resistance in MET Exon 14 Skipping Lung Cancer Using Patient-Derived Xenograft Models

Background Non-small cell lung cancer (NSCLC) driven by MET exon 14 skipping (METex14) occurs in 3-4% of NSCLC cases and defines a subset of patients with distinct characteristics. MET targeted therapy has led to strong clinical responses, however little is known about aquired resistance to drugs in these patients. Patient derived xenograft (PDX) models are recognized as excellent preclinical models to facilitate the understanding of the mechanisms underlying drug resistance. Methods We describe a patient case harboring METex14 who exhibited drug resistance after treatment with crizotinib. Subcutaneous xenografts were generated from pretreatment and post-resistance patient specimens. PDX mice were then treated with MET inhibitors (crizotinib and tepotinib) to evaluate their drug response. DNA and RNA sequencing analysis was performed on patient tumor specimens and matching xenografts. Results PDXs preserved most of the histological and molecular profiles of the parental tumors. Drug resistance to MET targeted therapy was confirmed in PDX models through in vivo drug analysis. Newly aquired MET D1228N mutations and EGFR amplificated were detected in patient-resistant tumor specimens. Although the mutations were not detected in the PDX, EGFR overexpression was observed in RNA sequencing analysis indicating possible off target resistance through the EGFR bypass signaling pathway. Conclusions We established and characterized a pair of METex14 NSCLC patient-derived xenografts (PDXs), including the first crizotinib resistant METex14 PDX. This model will be a powerful tool for testing hypotheses of drug resistance mechanisms and investigations into novel therapeutic strategies.