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Johnson N , Johnson SF , Yao W , Li YC , Choi YE , Bernhardy AJ , Wang YF , 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
Proceedings of the National Academy of Sciences of the United States of America. 2013 Oct;110(42) :17041-17046
PMID: WOS:000325634200073    PMCID: PMC 3801063   
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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.