TY  - JOUR
AU  - Noronha, Ashish
AU  - Belugali Nataraj, Nishanth
AU  - Sang Lee, Joo
AU  - Zhitomirsky, Benny
AU  - Oren, Yaara
AU  - Oster, Sara
AU  - Lindzen, Moshit
AU  - Mukherjee, Saptaparna
AU  - Will, Rainer
AU  - Ghosh, Soma
AU  - Simoni-Nieves, Arturo
AU  - Verma, Aakanksha
AU  - Chatterjee, Rishita
AU  - Borgoni, Simone
AU  - Robinson, Welles
AU  - Sinha, Sanju
AU  - Brandis, Alexander
AU  - Kerr, D Lucas
AU  - Wu, Wei
AU  - Sekar, Arunachalam
AU  - Giri, Suvendu
AU  - Chung, Youngmin
AU  - Drago-Garcia, Diana
AU  - Danysh, Brian P
AU  - Lauriola, Mattia
AU  - Fiorentino, Michelangelo
AU  - Ardizzoni, Andrea
AU  - Oren, Moshe
AU  - Blakely, Collin M
AU  - Ezike, Jideofor
AU  - Wiemann, Stefan
AU  - Parida, Laxmi
AU  - Bivona, Trever G
AU  - Aqeilan, Rami I
AU  - Brugge, Joan S
AU  - Regev, Aviv
AU  - Getz, Gad
AU  - Ruppin, Eytan
AU  - Yarden, Yosef
TI  - AXL and error-prone DNA replication confer drug resistance and offer strategies to treat EGFR-mutant lung cancer.
JO  - Cancer discovery
VL  - 12
IS  - 11
SN  - 2159-8274
CY  - Philadelphia, Pa.
M1  - DKFZ-2022-01582
SP  - 2666-2683
PY  - 2022
N1  - 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
AB  - 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.
LB  - PUB:(DE-HGF)16
C6  - pmid:35895872
DO  - DOI:10.1158/2159-8290.CD-22-0111
UR  - https://inrepo02.dkfz.de/record/180826
ER  -