Dual MET and ERBB inhibition overcomes intra-tumor plasticity in osimertinib resistant advanced non-small cell lung cancer (NSCLC)

Abstract

BackgroundThird-generation epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) such as osimertinib are the last line of targeted treatment for metastatic non-small cell lung cancer (NSCLC) EGFR-mutant harboring T790M. Different mechanisms of acquired resistance to third-generation EGFR-TKIs have been proposed. It is therefore crucial to identify new and effective strategies to overcome successive acquired mechanisms of resistance.MethodsFor Amplicon-seq analysis, samples from the index patient (primary and metastasis lesions at different timepoints) as well as the patient derived orthotopic xenograft (PDOX) tumors corresponding to the different treatment arms were used. All samples were formalin-fixed paraffin-embedded (FFPE), selected and evaluated by a pathologist. For ddPCR, twenty patients diagnosed with NSCLC at baseline or progression to different lines of TKI therapies were selected. FFPE blocks corresponding to either primary tumor or metastasis specimens were used for analysis. For single cell analysis orthotopically grown metastases were dissected from the brain of an athymic nu/nu mouse and cryopreserved at -80 °C.ResultsIn a brain metastasis lesion from a NSCLC patient presenting an EGFR T790M mutation we detected MET gene amplification after prolonged treatment with osimertinib. Importantly, the combination of capmatinib (c-MET inhibitor) and afatinib (ErbB-1/2/4 inhibitor) completely suppressed tumor growth in mice orthotopically injected with cells derived from this brain metastasis. In those mice treated with capmatinib or afatinib as monotherapy we observed the emergence of KRAS G12C clones. Single cell gene expression analyses also revealed intratumor heterogeneity, indicating the presence of a KRAS-driven subclone. We also detected low frequent KRAS G12C alleles in patients treated with various EGFR-TKIs.ConclusionAcquired resistance to subsequent EGFR TKI treatment lines in EGFR-mutant lung cancer patients may induce genetic plasticity. We assess the biological insights of tumor heterogeneity in an osimertinib-resistant tumor with acquired MET-amplification and propose new treatment strategies in this situation.

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