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posted on 2024-02-08, 14:20 authored by Nitin Roper, Rajaa El Meskini, Tapan Maity, Devon Atkinson, Amanda Day, Nathan Pate, Constance M. Cultraro, Svetlana Pack, Valerie Zgonc, Zoe Weaver Ohler, Udayan Guha Generation of spatial and temporally heterogenous osimertinib-resistant EGFR-mutant NSCLC PDX models and treatment study design. A, Schematic diagram of the prospective clinical trial of LAT for osimertinib-treated EGFR-mutant lung cancer (RT: radiotherapy). PDXs were generated from osimertinib-resistant tumor tissue either at first or second progression on osimertinib or after standard of care (S.O.C) therapy. B, Multi-region and temporal tumor samples from surgical resections or biopsies used for PDX generation are shown for each individual patient. Putative mechanism of resistance to osimertinib as evidenced by exome and or transcriptome sequencing (Roper et al., Cell Reports Medicine 2020) is shown below each set of PDXs. Color denotes timing of sample acquisition. Red: first progression on osimertinib; Green: second progression on osimertinib; Blue: progression on S.O.C treatment. C, Illustrations of PDX generation from 3 patients with EGFR-mutant lung cancer with MET polysomy by FISH (MET ≥ 4.0 and <6.0 copies/cell if MET/CEP7 ratio is <2) or MET amplification by FISH (MET/CEP7 ratio ≥2.0 or ≥6 MET copies per cell) as a mechanism of resistance to osimertinib. D, Study design for treatment with MET inhibitor (savolitinib) with a third-generation EGFR TKI (osimertinib). PDXs with spatial heterogeneity in MET pathway activation (LAT001_6B and LAT001_9B), PDXs with temporal heterogeneity in MET pathway activation (LAT006_2B and LAT006_0118) and an additional validation PDX (LAT015_6B) were treated with vehicle, osimertinib, savolitinib, and osimertinib plus savolitinib combination followed by assessment of efficacy and identification of predictive markers.
Funding
HHS | National Institutes of Health (NIH)
History
ARTICLE ABSTRACT
MET pathway activation is one of the most common mechanisms of resistance to osimertinib in EGFR-mutant non–small cell lung cancer (NSCLC). We previously demonstrated spatial and temporal heterogeneity in MET pathway activation upon osimertinib resistance in EGFR-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 EGFR-mutant NSCLC. MET pathway activation was a putative mechanism of osimertinib resistance in 66% (n = 6/9) patients from whom PDXs were generated. Significant spatial and temporal heterogeneity in MET pathway activation was evident. Osimertinib-resistant PDXs with MET amplification by FISH (defined as MET/CEP7 ratio ≥2.0 or mean MET ≥ 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. MET polysomy tumors by FISH from both PDXs and patients had evidence of subclonal phospho-MET expression. Select MET polysomy PDX tumors with phospho-MET expression responded better to osimertinib and savolitinib combination than MET polysomy PDX tumors without phospho-MET expression. Our results suggest osimertinib and savolitinib combination is most effective for osimertinib-resistant EGFR-mutant tumors with MET pathway activation as evidenced by phospho-MET. As subclonal MET amplification may be evident in MET polysomy tumor progression, MET polysomy warrants close clinical follow-up with phospho-MET IHC in parallel with FISH diagnostic.
Using a novel cohort of in vivo 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 MET polysomy tumors may have subclonal MET amplification and therefore require close follow up for the use of osimertinib and savolitinib combination.
