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Published (Version of record)CC BY-NC-ND V4.0, Open Access
Published (Version of record)CC BY-NC-ND V4.0, Open Access
Journal article
AXL and error-prone DNA replication confer drug resistance and offer strategies to treat EGFR-mutant lung cancer
Cancer discovery, Vol.12(11), pp.2667-2683
27/Jul/2022
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.
Details
- Title
- AXL and error-prone DNA replication confer drug resistance and offer strategies to treat EGFR-mutant lung cancer
- Creators
- Ashish NoronhaNishanth Belugali Nataraj - 972WIS_INST___120Joo Sang Lee - National Cancer InstituteBenny Zhitomirsky - Broad InstituteYaara Oren - Broad InstituteSara Oster - Hebrew University of JerusalemMoshit Lindzen - 972WIS_INST___120Saptaparna Mukherjee - 972WIS_INST___122Rainer Will - German Cancer Research CenterSoma Ghosh - Weizmann Institute of ScienceArturo Simoni-Nieves - Weizmann Institute of ScienceAakanksha Verma - 972WIS_INST___120Rishita Chatterjee - 972WIS_INST___120Simone Borgoni - German Cancer Research CenterWelles Robinson - National Cancer InstituteSanju Sinha - National Cancer InstituteAlexander Brandis - 972WIS_INST___113D Lucas Kerr - University of California, San FranciscoWei Wu - University of California, San FranciscoArunachalam Sekar - 972WIS_INST___120Suvendu Giri - 972WIS_INST___120Youngmin Chung - Sungkyunkwan UniversityDiana Drago-Garcia - 972WIS_INST___120Brian P Danysh - Broad InstituteMattia Lauriola - University of BolognaMichelangelo Fiorentino - University of BolognaAndrea Ardizzoni - University of BolognaMoshe Oren - 972WIS_INST___122Collin M Blakely - University of California, San FranciscoJideofor Ezike - Broad InstituteStefan WiemannLaxmi ParidaTrever G Bivona - University of California, San FranciscoRami I Aqeilan - Hebrew University of JerusalemJoan S Brugge - Harvard UniversityAviv Regev - 972WIS_INST___abb92f2c-748b-4cc7-957f-81b9934edb1bGad Getz - Broad InstituteEytan Ruppin - National Cancer InstituteYosef Yarden - 972WIS_INST___120
- Resource Type
- Journal article
- Publication Details
- Cancer discovery, Vol.12(11), pp.2667-2683; 27/Jul/2022
- Number of pages
- 18
- Language
- English
- DOI
- https://doi.org/10.1158/2159-8290.CD-22-0111
- Grant note
- We thank Tomer Meir Salame, Tevi Mehlman, Orit Leitner, Hedva Hamawi, Gilgi Friedlander, and Roni Oren for methodologic help and advice and Moshe Elkabets for reagents. This work was performed in the Marvin Tanner Laboratory for Research on Cancer. Y. Yarden is the incumbent of the Harold and Zelda Goldenberg Professorial Chair in Molecular Cell Biology. Our studies are supported by the Israel Science Foundation (ISF; 1931/20), the European Research Council (ERC; 740469), and the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation (AMRF; to M. Oren, J.S. Brugge, G. Getz, and Y. Yarden). Funding for sequencing and fellowships of B. Zhitomirsky and B.P. Danysh was provided by the Broad/IBM Cancer Resistance Research Project (given to G. Getz and L. Parida). Y. Oren was supported by the Hope Fund for Cancer Research, Grillo-Marxuach Postdoctoral Fellowship, and the Rivkin Scientific Scholar Award. Grant no. 740469
- Record Identifier
- 993400983203596
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