title: EGFR-activating mutations correlate with a Fanconi anemia-like cellular phenotype that includes PARP inhibitor sensitivity.
abstract: In patients with lung cancer whose tumors harbor activating mutations in the EGF receptor (EGFR), increased responses to platinum-based chemotherapies are seen compared with wild-type cancers. However, the mechanisms underlying this association have remained elusive. Here, we describe a cellular phenotype of cross-linker sensitivity in a subset of EGFR-mutant lung cancer cell lines that is reminiscent of the defects seen in cells impaired in the Fanconi anemia pathway, including a pronounced G2-M cell-cycle arrest and chromosomal radial formation. We identified a defect downstream of FANCD2 at the level of recruitment of FAN1 nuclease and DNA interstrand cross-link (ICL) unhooking. The effect of EGFR mutation was epistatic with FANCD2. Consistent with the known role of FANCD2 in promoting RAD51 foci formation and homologous recombination repair (HRR), EGFR-mutant cells also exhibited an impaired RAD51 foci response to ICLs, but not to DNA double-strand breaks. EGFR kinase inhibition affected RAD51 foci formation neither in EGFR-mutant nor wild-type cells. In contrast, EGFR depletion or overexpression of mutant EGFR in wild-type cells suppressed RAD51 foci, suggesting an EGFR kinase-independent regulation of DNA repair. Interestingly, EGFR-mutant cells treated with the PARP inhibitor olaparib also displayed decreased FAN1 foci induction, coupled with a putative block in a late HRR step. As a result, EGFR-mutant lung cancer cells exhibited olaparib sensitivity in vitro and in vivo. Our findings provide insight into the mechanisms of cisplatin and PARP inhibitor sensitivity of EGFR-mutant cells, yielding potential therapeutic opportunities for further treatment individualization in this genetically defined subset of lung cancer.
authors: Authors' Affiliations: Laboratory of Cellular & Molecular Radiation Oncology, Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Charlestown; Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston; and Center for Cancer Research, Massachusetts General Hospital Cancer Center, Charlestown, Massachusetts; Research Oncology, Genentech, Inc., South San Francisco, California; Department of Pharmaceutical Biology, Ludwig Maximilian University of Munich, Munich; and Center for Oncology, University Medical Center Hamburg-Eppendorf, University of Hamburg, Hamburg, Germany.
authors: Heike N
authors: HN
authors: Pfäffle
authors: Meng
authors: M
authors: Wang
authors: Liliana
authors: L
authors: Gheorghiu
authors: Natalie
authors: N
authors: Ferraiolo
authors: Patricia
authors: P
authors: Greninger
authors: Kerstin
authors: K
authors: Borgmann
authors: Jeffrey
authors: J
authors: Settleman
authors: Cyril H
authors: CH
authors: Benes
authors: Lecia V
authors: LV
authors: Sequist
authors: Lee
authors: L
authors: Zou
authors: Henning
authors: H
authors: Willers
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology; D004706:Endodeoxyribonucleases; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D066246:ErbB Receptors / Q000235:genetics* / Q000378:metabolism; D005090:Exodeoxyribonucleases / Q000235:genetics / Q000378:metabolism; D005199:Fanconi Anemia / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D052236:Fanconi Anemia Complementation Group D2 Protein / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008175:Lung Neoplasms / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D051379:Mice; D064251:Multifunctional Enzymes; D009154:Mutation; D041681:NIH 3T3 Cells; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics; D051135:Rad51 Recombinase / Q000235:genetics / Q000378:metabolism; D011995:Recombination, Genetic; D015398:Signal Transduction; D014162:Transfection
chemical_list: D004791:Enzyme Inhibitors; C499905:FANCD2 protein, human; D052236:Fanconi Anemia Complementation Group D2 Protein; D064251:Multifunctional Enzymes; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases; D066246:ErbB Receptors; C495153:RAD51 protein, human; D051135:Rad51 Recombinase; D004706:Endodeoxyribonucleases; D005090:Exodeoxyribonucleases; C551063:FAN1 protein, human; D002945:Cisplatin
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