Novel syngeneic models for evaluating therapies targeting EGFR L858R/T790M and EGFR L858R/T790M/C979S resistance mutations in NSCLC

Both the first and second-generation EGFR-TKIs drugs have markedly improved the survival of NSCLC patients with activating EGFR mutations. However a secondary T790M mutation rapidly drives resistance towards these drugs. Third-generation EGFR-TKIs potently suppress the T790M mutant, but the subsequent C797S mutation abolishes their covalent binding, leaving no currently approved targeted options. Therefore, our laboratory generated conditional knock-in C57BL/6 mice harboring human EGFR L858R/T790M or EGFR L858R/T790M/C979S , which quickly develop spontaneous NSCLC and yield primary tumor cell lines.In syngeneic, immune-competent C57BL/6 hosts, the fourth-generation TKI under research, BLU-945, markedly inhibited both EGFR L858R/T790M and EGFR L858R/T790M/C979S tumor growth. In contrast, osimertinib was effective only against EGFR L858R/T790M , but failing against the EGFR L858R/T790M/C979S mutation. This demonstrates how our novel mouse models faithfully recapitulate and allow the reversal of osimertinib resistance in vivo .