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000180826 1001_ $$00000-0002-3415-6113$$aNoronha, Ashish$$b0
000180826 245__ $$aAXL and error-prone DNA replication confer drug resistance and offer strategies to treat EGFR-mutant lung cancer.
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000180826 500__ $$a2022 Nov 2;12(11):2666-2683 / Genomics and Proteomics Core Facility, German Cancer Research Center (DKFZ), ImNeuenheimer Feld 580, 69120, Heidelberg, GermanyDivision of Molecular Genome Analysis, German Cancer Research Center (DKFZ), ImNeuenheimer Feld 580, 69120, Heidelberg, Germany
000180826 520__ $$aAnti-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.
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000180826 7001_ $$00000-0003-2970-6739$$aBelugali Nataraj, Nishanth$$b1
000180826 7001_ $$00000-0001-8564-0848$$aSang Lee, Joo$$b2
000180826 7001_ $$00000-0002-8027-927X$$aZhitomirsky, Benny$$b3
000180826 7001_ $$00000-0002-2509-4504$$aOren, Yaara$$b4
000180826 7001_ $$00000-0002-4121-7754$$aOster, Sara$$b5
000180826 7001_ $$00000-0002-4485-1355$$aLindzen, Moshit$$b6
000180826 7001_ $$00000-0002-8704-481X$$aMukherjee, Saptaparna$$b7
000180826 7001_ $$0P:(DE-He78)18218139eec55d83cf82679934e5cd75$$aWill, Rainer$$b8$$udkfz
000180826 7001_ $$aGhosh, Soma$$b9
000180826 7001_ $$00000-0002-1353-260X$$aSimoni-Nieves, Arturo$$b10
000180826 7001_ $$00000-0001-9827-9457$$aVerma, Aakanksha$$b11
000180826 7001_ $$00000-0001-8484-3897$$aChatterjee, Rishita$$b12
000180826 7001_ $$0P:(DE-He78)e635cab0f60a8b5551c6dd7a8b3f7c06$$aBorgoni, Simone$$b13
000180826 7001_ $$00000-0001-9018-6811$$aRobinson, Welles$$b14
000180826 7001_ $$00000-0002-2688-0603$$aSinha, Sanju$$b15
000180826 7001_ $$00000-0001-9604-2229$$aBrandis, Alexander$$b16
000180826 7001_ $$00000-0002-0557-8341$$aKerr, D Lucas$$b17
000180826 7001_ $$00000-0002-6556-067X$$aWu, Wei$$b18
000180826 7001_ $$00000-0002-4659-5260$$aSekar, Arunachalam$$b19
000180826 7001_ $$00000-0002-7595-1359$$aGiri, Suvendu$$b20
000180826 7001_ $$00000-0002-0597-1004$$aChung, Youngmin$$b21
000180826 7001_ $$00000-0001-6397-3123$$aDrago-Garcia, Diana$$b22
000180826 7001_ $$00000-0001-6839-6337$$aDanysh, Brian P$$b23
000180826 7001_ $$00000-0002-7966-0065$$aLauriola, Mattia$$b24
000180826 7001_ $$00000-0002-1749-150X$$aFiorentino, Michelangelo$$b25
000180826 7001_ $$00000-0003-2678-0714$$aArdizzoni, Andrea$$b26
000180826 7001_ $$00000-0003-4311-7172$$aOren, Moshe$$b27
000180826 7001_ $$00000-0001-8134-3651$$aBlakely, Collin M$$b28
000180826 7001_ $$00000-0002-3767-8902$$aEzike, Jideofor$$b29
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000180826 7001_ $$00000-0002-7872-5074$$aParida, Laxmi$$b31
000180826 7001_ $$00000-0001-5734-4128$$aBivona, Trever G$$b32
000180826 7001_ $$00000-0002-6034-023X$$aAqeilan, Rami I$$b33
000180826 7001_ $$00000-0002-2547-4814$$aBrugge, Joan S$$b34
000180826 7001_ $$00000-0003-3293-3158$$aRegev, Aviv$$b35
000180826 7001_ $$00000-0002-0936-0753$$aGetz, Gad$$b36
000180826 7001_ $$00000-0002-7862-3940$$aRuppin, Eytan$$b37
000180826 7001_ $$00000-0003-4168-7884$$aYarden, Yosef$$b38
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