AXL and Error-Prone DNA Replication Confer Drug Resistance and Offer Strategies to Treat EGFR-Mutant Lung Cancer

Ashish Noronha, Nishanth Belugali Nataraj, Joo Sang Lee, Benny Zhitomirsky, Yaara Oren, Sara Oster, Moshit Lindzen, Saptaparna Mukherjee, Rainer Will, Soma Ghosh, Arturo Simoni-Nieves, Aakanksha Verma, Rishita Chatterjee, Simone Borgoni, Welles Robinson, Sanju Sinha, Alexander Brandis, D. Lucas Kerr, Wei Wu, Arunachalam SekarSuvendu Giri, Youngmin Chung, Diana Drago-Garcia, Brian P. Danysh, Mattia Lauriola, Michelangelo Fiorentino, Andrea Ardizzoni, Moshe Oren, Collin M. Blakely, Jideofor Ezike, Stefan Wiemann, Laxmi Parida, Trever G. Bivona, Rami I. Aqeilan, Joan S. Brugge, Aviv Regev, Gad Getz, Eytan Ruppin, Yosef Yarden*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

43 Scopus citations

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. SIGNIFICANCE: 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.

Original languageAmerican English
Pages (from-to)2666-2683
Number of pages18
JournalCancer Discovery
Volume12
Issue number11
DOIs
StatePublished - 2 Nov 2022

Bibliographical note

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© 2022, American Association for Cancer Research Inc.. All rights reserved.

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