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Novel Mechanisms of PARP Inhibitor Resistance in BRCA1-Deficient Breast Cancers

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Technical Report,01 Dec 2014,30 Nov 2015

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Massachusetts General Hospital Boston United States

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Mutations in the BRCA1 gene are associated with a heightened lifetime risk for breast cancer. PARP inhibitors PARPi have been tested with promising results for the treatment of BRCA1-associated cancers. BRCA1 is essential for error-free repair of DNA double strand breaks via homologous recombination HR, while PARPs are thought to primarily function in repair of single stranded DNA breaks especially through activation of base excision repair BER. A synthetic lethal phenotype occurs when BRCA1- deficiency HR deficiency is combined with PARPi BER defect. However, a majority of BRCA1-deficient tumors do not respond to PARPi, and, of those that do, all tumors recur. I aim to 1 To determine how HR is rescued in BRCA1-deficient cells 2 to elucidate HR-independent mechanisms of PARPi resistance 3 to elucidate means of targeting PARPi resistant cancers. I have found the ATRi can synergize with PARPi to resensitize BRCA1-deficient cells to PARPi by preventing Rad51 loading in HR and fork protection. The results of this project may be broadly applicable to BRCA-like and other non-hereditary, spontaneous breast cancers, including triple negative breast cancers. Ultimately, the proposed experiments will provide an understanding of the mechanisms of acquired resistance to PARPi treatment and how resistant tumors can be categorized and targeted for treatment.

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