Stabilization of mutant BRCA1 protein confers PARP inhibitor and platinum resistance

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 110; no. 42; pp. 17041 - 17046
• 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 National Academy of Sciences 15.10.2013; NATIONAL ACADEMY OF SCIENCES; National Acad Sciences
• Subjects: Adenosine diphosphate; animal ovaries; Antineoplastic Agents - pharmacology; Benzoquinones - pharmacology; Biological Sciences; BRCA proteins; BRCA1 Protein - genetics; BRCA1 Protein - metabolism; BRCA2 Protein - genetics; BRCA2 Protein - metabolism; Breast cancer; breast neoplasms; carcinoma; Cell Line, Tumor; Cell lines; Cells; Cellular immunity; cisplatin; Cisplatin - pharmacology; Deoxyribonucleic acid; DNA; DNA polymerase; DNA repair; Drug Resistance, Neoplasm - drug effects; Drug Resistance, Neoplasm - genetics; Fanconi Anemia Complementation Group N Protein; Female; Genetic mutation; HSP90 Heat-Shock Proteins - antagonists & inhibitors; HSP90 Heat-Shock Proteins - genetics; HSP90 Heat-Shock Proteins - metabolism; Humans; Lactams, Macrocyclic - pharmacology; Mutants; Mutation; NAD ADP-ribosyltransferase; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; Ovarian Neoplasms - drug therapy; Ovarian Neoplasms - genetics; Ovarian Neoplasms - metabolism; Ovarian Neoplasms - pathology; Platinum; Platinum - pharmacology; Poly(ADP-ribose) Polymerase Inhibitors; Poly(ADP-ribose) Polymerases - genetics; Poly(ADP-ribose) Polymerases - metabolism; protein products; Protein Structure, Tertiary; protein synthesis; Proteins; Rad51 Recombinase - genetics; Rad51 Recombinase - metabolism; resection; Small interfering RNA; tumor suppressor proteins; Tumor Suppressor Proteins - genetics; Tumor Suppressor Proteins - metabolism; Tumors; homologous recombination; cancer therapy
• ISSN: 0027-8424; 1091-6490; 1091-6490
• DOI: 10.1073/pnas.1305170110

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.