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@ARTICLE{Noronha:180826,
      author       = {A. Noronha and N. Belugali Nataraj and J. Sang Lee and B.
                      Zhitomirsky and Y. Oren and S. Oster and M. Lindzen and S.
                      Mukherjee and R. Will$^*$ and S. Ghosh and A. Simoni-Nieves
                      and A. Verma and R. Chatterjee and S. Borgoni$^*$ and W.
                      Robinson and S. Sinha and A. Brandis and D. L. Kerr and W.
                      Wu and A. Sekar and S. Giri and Y. Chung and D. Drago-Garcia
                      and B. P. Danysh and M. Lauriola and M. Fiorentino and A.
                      Ardizzoni and M. Oren and C. M. Blakely and J. Ezike and S.
                      Wiemann$^*$ and L. Parida and T. G. Bivona and R. I. Aqeilan
                      and J. S. Brugge and A. Regev and G. Getz and E. Ruppin and
                      Y. Yarden},
      title        = {{AXL} and error-prone {DNA} replication confer drug
                      resistance and offer strategies to treat {EGFR}-mutant lung
                      cancer.},
      journal      = {Cancer discovery},
      volume       = {12},
      number       = {11},
      issn         = {2159-8274},
      address      = {Philadelphia, Pa.},
      reportid     = {DKFZ-2022-01582},
      pages        = {2666-2683},
      year         = {2022},
      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},
      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.},
      cin          = {B050 / W111},
      ddc          = {610},
      cid          = {I:(DE-He78)B050-20160331 / I:(DE-He78)W111-20160331},
      pnm          = {312 - Funktionelle und strukturelle Genomforschung
                      (POF4-312)},
      pid          = {G:(DE-HGF)POF4-312},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:35895872},
      doi          = {10.1158/2159-8290.CD-22-0111},
      url          = {https://inrepo02.dkfz.de/record/180826},
}