Journal Article

DKFZ-2022-01582

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png AXL and error-prone DNA replication confer drug resistance and offer strategies to treat EGFR-mutant lung cancer.

Noronha, A. ; Belugali Nataraj, N. ; Sang Lee, J. ; Zhitomirsky, B. ; Oren, Y. ; Oster, S. ; Lindzen, M. ; Mukherjee, S. ; Will, R.DKFZ* ; Ghosh, S. ; Simoni-Nieves, A. ; Verma, A. ; Chatterjee, R. ; Borgoni, S.DKFZ* ; Robinson, W. ; Sinha, S. ; Brandis, A. ; Kerr, D. L. ; Wu, W. ; Sekar, A. ; Giri, S. ; Chung, Y. ; Drago-Garcia, D. ; Danysh, B. P. ; Lauriola, M. ; Fiorentino, M. ; Ardizzoni, A. ; Oren, M. ; Blakely, C. M. ; Ezike, J. ; Wiemann, S.DKFZ* ; Parida, L. ; Bivona, T. G. ; Aqeilan, R. I. ; Brugge, J. S. ; Regev, A. ; Getz, G. ; Ruppin, E. ; Yarden, Y.

2022
Philadelphia, Pa.

This record in other databases:  

Please use a persistent id in citations: doi:10.1158/2159-8290.CD-22-0111

Abstract: 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 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, while 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.

Note: 2022 Nov 2;12(11):2666-2683 / Genomics and Proteomics Core Facility, German Cancer Research Center (DKFZ), ImNeuenheimer Feld 580, 69120, Heidelberg, GermanyDivision of Molecular Genome Analysis, German Cancer Research Center (DKFZ), ImNeuenheimer Feld 580, 69120, Heidelberg, Germany

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Contributing Institute(s):

1. B050 Molekulare Genomanalyse (B050)
2. Zelluläre Tools (W111)

Research Program(s):

1. 312 - Funktionelle und strukturelle Genomforschung (POF4-312) (POF4-312)

Appears in the scientific report 2022

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Database coverage:
; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Essential Science Indicators ; IF >= 30 ; JCR ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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