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Johnson N , Johnson SF , Yao W , Li YC , Choi YE , Bernhardy AJ , Wang Y , Capelletti M , Sarosiek KA , Moreau LA , Chowdhury D , Wickramanayake A , Harrell MI , Liu JF , D'Andrea AD , Miron A , Swisher EM , Shapiro GI
Stabilization of mutant BRCA1 protein confers PARP inhibitor and platinum resistance
Proc Natl Acad Sci U S A. 2013 Oct 15;110(42) :17041-6
PMID: 24085845    PMCID: PMC 3801063    URL: https://www.ncbi.nlm.nih.gov/pubmed/24085845
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Breast Cancer Type 1 Susceptibility Protein (BRCA1)-deficient cells have compromised DNA repair and are sensitive to poly(ADP-ribose) polymerase (PARP) inhibitors. Despite initial responses, the development of resistance limits clinical efficacy. Mutations in the BRCA C-terminal (BRCT) domain of BRCA1 frequently create protein products unable to fold that are subject to protease-mediated degradation. Here, we show HSP90-mediated stabilization of a BRCT domain mutant BRCA1 protein under PARP inhibitor selection pressure. The stabilized mutant BRCA1 protein interacted with PALB2-BRCA2-RAD51, was essential for RAD51 focus formation, and conferred PARP inhibitor as well as cisplatin resistance. Treatment of resistant cells with the HSP90 inhibitor 17-dimethylaminoethylamino-17-demethoxygeldanamycin reduced mutant BRCA1 protein levels and restored their sensitivity to PARP inhibition. Resistant cells also acquired a TP53BP1 mutation that facilitated DNA end resection in the absence of a BRCA1 protein capable of binding CtIP. Finally, concomitant increased mutant BRCA1 and decreased 53BP1 protein expression occur in clinical samples of BRCA1-mutated recurrent ovarian carcinomas that have developed resistance to platinum. These results provide evidence for a two-event mechanism by which BRCA1-mutant tumors acquire anticancer therapy resistance.
Johnson, Neil Johnson, Shawn F Yao, Wei Li, Yu-Chen Choi, Young-Eun Bernhardy, Andrea J Wang, Yifan Capelletti, Marzia Sarosiek, Kristopher A Moreau, Lisa A Chowdhury, Dipanjan Wickramanayake, Anneka Harrell, Maria I Liu, Joyce F D'Andrea, Alan D Miron, Alexander Swisher, Elizabeth M Shapiro, Geoffrey I eng P50 CA83636/CA/NCI NIH HHS/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Proc Natl Acad Sci U S A. 2013 Oct 15;110(42):17041-6. doi: 10.1073/pnas.1305170110. Epub 2013 Oct 1.