Dissecting the Mechanisms of Drug Resistance in BRCA1/2-Mutant Breast Cancers
Technical Report,30 Sep 2017,29 Sep 2018
Dana-Farber Cancer Institute Boston United States
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PolyADP-ribose polymerase PARP inhibition provides a promising therapeutic modality for targeting homologous recombination HRdeficient tumors such as BRCA1 and BRCA2-mutated triple negative breast cancers TNBCs. Although PARP inhibitors have shown activity in the BRCA-associated TNBCs, several of these tumors develop de novo as well as acquired PARP inhibitor PARPi resistance. Besides attenuation in intracellular uptake of drugs, the only known mechanism that drives chemotherapy resistance of BRCA12-deficient cancers is through the restoration of HR. Recent studies from our laboratories Nussenzweig and DAndrea indicate that deregulation of pathways that promote extensive degradation of nascent DNA strands and alternative end-joining Alt-EJ can render BRCA12-deficient cells resistant to PARPi in a HR-independent manner. The objective of our project is to collaboratively test the hypothesis that complex processes involving Alt-EJ or replication fork stability promote survival and drive resistance to chemotherapy. A detailed assessment of the critical mediators that regulate the balance between HR, Alt-EJ and replication fork degradation should identify novel means to overcome acquired chemo resistance in BRCA12-mutated breast cancers. During the second year of the DOD funding, we have made significant progress in clarifying mechanisms and identifying proteins which could contribute to replication fork stability and chemo resistance in BRCA2-deficient tumors.
- Medicine and Medical Research