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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Published in:Proceedings of the National Academy of Sciences - PNAS Vol. 110; no. 42; p. 17041
Main Authors: 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
Language:English
Published: United States 15.10.2013
Subjects:
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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Summary: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.
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ISSN:1091-6490
1091-6490
DOI:10.1073/pnas.1305170110