Stabilization of mutant BRCA1 protein confers PARP inhibitor and platinum resistance

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 BRC...

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Veröffentlicht in:	Proceedings of the National Academy of Sciences - PNAS Jg. 110; H. 42; S. 17041
Hauptverfasser:	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
Format:	Journal Article
Sprache:	Englisch
Veröffentlicht:	United States 15.10.2013
Schlagworte:	Antineoplastic Agents - pharmacology Benzoquinones - pharmacology BRCA1 Protein - genetics BRCA1 Protein - metabolism BRCA2 Protein - genetics BRCA2 Protein - metabolism Cell Line, Tumor Cisplatin - pharmacology Drug Resistance, Neoplasm - drug effects Drug Resistance, Neoplasm - genetics Fanconi Anemia Complementation Group N Protein Female HSP90 Heat-Shock Proteins - antagonists & inhibitors HSP90 Heat-Shock Proteins - genetics HSP90 Heat-Shock Proteins - metabolism Humans Lactams, Macrocyclic - pharmacology Mutation Nuclear Proteins - genetics Nuclear Proteins - metabolism Ovarian Neoplasms - drug therapy Ovarian Neoplasms - genetics Ovarian Neoplasms - metabolism Ovarian Neoplasms - pathology Platinum - pharmacology Poly(ADP-ribose) Polymerase Inhibitors Poly(ADP-ribose) Polymerases - genetics Poly(ADP-ribose) Polymerases - metabolism Protein Structure, Tertiary Rad51 Recombinase - genetics Rad51 Recombinase - metabolism Tumor Suppressor Proteins - genetics Tumor Suppressor Proteins - metabolism homologous recombination cancer therapy
ISSN:	1091-6490, 1091-6490
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Zusammenfassung:	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.
Bibliographie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1091-6490 1091-6490
DOI:	10.1073/pnas.1305170110