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- W4288052521 abstract "Anticancer therapies have been limited by the 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 the treatment of lung cancer with EGFR inhibitors (EGFRi) similarly engages hypermutators. In cycling drug-tolerant persister (DTP) cells and in EGFRi-treated patients presenting residual disease, we observed upregulation of GAS6, whereas ablation of GAS6's receptor, AXL, eradicated resistance. 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 cured patient-derived xenografts. Hence, similar to bacteria, tumors tolerate therapy by engaging pharmacologically targetable endogenous mutators.EGFR-mutant lung cancers treated with kinase inhibitors often evolve resistance due to secondary mutations. We report that in similarity to the bacterial SOS response stimulated by antibiotics, endogenous mutators are activated in drug-treated cells, and this heralds tolerance. Blocking the process prevented resistance in xenograft models, which offers new treatment strategies. This article is highlighted in the In This Issue feature, p. 2483." @default.
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- W4288052521 date "2022-07-27" @default.
- W4288052521 modified "2023-10-05" @default.
- W4288052521 title "AXL and Error-Prone DNA Replication Confer Drug Resistance and Offer Strategies to Treat EGFR-Mutant Lung Cancer" @default.
- W4288052521 cites W1778149359 @default.
- W4288052521 cites W1819499229 @default.
- W4288052521 cites W1968291566 @default.
- W4288052521 cites W1974875206 @default.
- W4288052521 cites W1983774108 @default.
- W4288052521 cites W1985264867 @default.
- W4288052521 cites W1998971866 @default.
- W4288052521 cites W2002937040 @default.
- W4288052521 cites W2003984225 @default.
- W4288052521 cites W2009569524 @default.
- W4288052521 cites W2048699088 @default.
- W4288052521 cites W2052005627 @default.
- W4288052521 cites W2054133698 @default.
- W4288052521 cites W2083870593 @default.
- W4288052521 cites W2091083398 @default.
- W4288052521 cites W2103770333 @default.
- W4288052521 cites W2103980474 @default.
- W4288052521 cites W2106391833 @default.
- W4288052521 cites W2106578986 @default.
- W4288052521 cites W2113711383 @default.
- W4288052521 cites W2121289930 @default.
- W4288052521 cites W2140334822 @default.
- W4288052521 cites W2165860917 @default.
- W4288052521 cites W2169950973 @default.
- W4288052521 cites W2172697812 @default.
- W4288052521 cites W2258318060 @default.
- W4288052521 cites W2272802268 @default.
- W4288052521 cites W2277421940 @default.
- W4288052521 cites W2471185287 @default.
- W4288052521 cites W2474755441 @default.
- W4288052521 cites W2607349660 @default.
- W4288052521 cites W2613056759 @default.
- W4288052521 cites W2773830451 @default.
- W4288052521 cites W2774267942 @default.
- W4288052521 cites W2785797026 @default.
- W4288052521 cites W2789435487 @default.
- W4288052521 cites W2800392061 @default.
- W4288052521 cites W2802173235 @default.
- W4288052521 cites W2809980410 @default.
- W4288052521 cites W2887301398 @default.
- W4288052521 cites W2898302238 @default.
- W4288052521 cites W2903802773 @default.
- W4288052521 cites W2904174314 @default.
- W4288052521 cites W2905535015 @default.
- W4288052521 cites W2910264472 @default.
- W4288052521 cites W2922021678 @default.
- W4288052521 cites W2968818167 @default.
- W4288052521 cites W2987148655 @default.
- W4288052521 cites W3017413818 @default.
- W4288052521 cites W3033942938 @default.
- W4288052521 cites W3078555423 @default.
- W4288052521 cites W3082983968 @default.
- W4288052521 cites W3086639494 @default.
- W4288052521 cites W3158204265 @default.