Data from Functional Heterogeneity in MET Pathway Activation in PDX Models of Osimertinib-resistant EGFR-driven Lung Cancer

Abstract

<div>Abstract<p>MET pathway activation is one of the most common mechanisms of resistance to osimertinib in <i>EGFR</i>-mutant non–small cell lung cancer (NSCLC). We previously demonstrated spatial and temporal heterogeneity in MET pathway activation upon osimertinib resistance in <i>EGFR</i>-mutant NSCLC; however, the functional relevance of these findings is unclear. Here, we generated 19 patient-derived xenografts (PDX) from 9 patients with multi-region and temporal sampling of osimertinib-resistant tumor tissue from patients with <i>EGFR</i>-mutant NSCLC. MET pathway activation was a putative mechanism of osimertinib resistance in 66% (<i>n</i> = 6/9) patients from whom PDXs were generated. Significant spatial and temporal heterogeneity in MET pathway activation was evident. Osimertinib-resistant PDXs with <i>MET</i> amplification by FISH (defined as <i>MET/CEP7</i> ratio ≥2.0 or mean <i>MET</i> ≥ 6.0 copies/cell) and high-level phospho-MET, but not c-MET expression, had better responses to osimertinib and savolitinib combination than to osimertinib alone. <i>MET</i> polysomy tumors by FISH from both PDXs and patients had evidence of subclonal phospho-MET expression. Select <i>MET</i> polysomy PDX tumors with phospho-MET expression responded better to osimertinib and savolitinib combination than <i>MET</i> polysomy PDX tumors without phospho-MET expression. Our results suggest osimertinib and savolitinib combination is most effective for osimertinib-resistant <i>EGFR</i>-mutant tumors with MET pathway activation as evidenced by phospho-MET. As subclonal <i>MET</i> amplification may be evident in <i>MET</i> polysomy tumor progression, <i>MET</i> polysomy warrants close clinical follow-up with phospho-MET IHC in parallel with FISH diagnostic.</p>Significance:<p>Using a novel cohort of <i>in vivo</i> PDX models of MET pathway activation with acquired resistance to osimertinib in EGFR-mutant lung cancer, we demonstrate that phospho-MET may be a clinically relevant assay to guide treatment selection with osimertinib and savolitinib combination. In addition, our work shows that patients with <i>MET</i> polysomy tumors may have subclonal <i>MET</i> amplification and therefore require close follow up for the use of osimertinib and savolitinib combination.</p></div>