Integrative genomic analysis of drug resistance in exon 14 skipping lung cancer using patient-derived xenograft models.

Background: Non-small cell lung cancer (NSCLC) driven by exon 14 skipping (ex14) occurs in 3-4% of NSCLC cases and defines a subset of patients with distinct characteristics. While MET targeted therapy has led to strong clinical results in ex14 patients, acquired drug resistance seemed to be unavoidable during treatment. Limited information is available regarding acquired resistance during MET targeted therapy, nor has there been any report on such patient-derived xenografts (PDXs) model facilitating the research.

Methods: We describe a patient case harboring ex14 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) and EGFR-MET bispecific antibodies (EMB-01 and amivantamab) 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 drug analysis. Newly acquired D1228H mutations and 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. As expected, EGFR-MET bispecific antibodies overcome drug resistant in the PDX model.

Conclusions: We detected a novel MET splice site deletion mutation that could lead to ex14. We also established and characterized a pair of ex14 NSCLC PDXs, including the first crizotinib resistant ex14 PDX. And dual inhibition of MET and EGFR might be a therapeutic strategy for EGFR-driven drug resistance ex14 lung cancer.