Resistance of Lung Cancer to Kinase Inhibitors Involves Activation of Endogenous Mutators

Anti-cancer therapies have been limited by emergence of mutations and other adaptations. In bacteria, antibiotics activate the SOS response, which mobilizes error‐prone factors that allow for continuous replication at the cost of mutagenesis. We investigated whether treatment of lung cancer harboring mutant EGFRs with tyrosine kinase inhibitors (TKI) similarly engages hypermutators. Our previous study proposed that drug-tolerant persister (DTP) cells, which give rise to mutation-bearing resister cells, elevate markers of the epithelial-mesenchymal transition (EMT), including up-regulation of GAS6 and its receptor, AXL. Consistent with this finding, we found that EGFRi-treated patients presenting residual disease display upregulation of GAS6, and ablation of AXL eradicated resistance in an animal model of lung cancer. Reciprocally, AXL overexpression enhanced DTP survival and accelerated the emergence of T790M, an EGFR mutation typical to resistant cells. Mechanistically, AXL induces low-fidelity DNA polymerases and activates their organizer, RAD18, by promoting neddylation. Metabolomics uncovered another hypermutator, AXL-driven activation of MYC and increased purine synthesis that is unbalanced by pyrimidines. Aligning anti-AXL combination treatments with the transition from DTPs to resistant cells prevented relapses of patient-derived xenografts in mice. Hence, similar to bacteria, tumors appear to tolerate therapy by engaging endogenous mutators, some of which might be pharmacologically targetable.