Accession Number : AD1047162


Title :   Dissecting the Mechanisms of Drug Resistance in BRCA1/2-Mutant Breast Cancers


Descriptive Note : Technical Report,30 Sep 2016,29 Sep 2017


Corporate Author : Dana-Farber Cancer Institute Inc. Boston United States


Personal Author(s) : D'Andrea, Alan


Full Text : https://apps.dtic.mil/dtic/tr/fulltext/u2/1047162.pdf


Report Date : 01 Oct 2017


Pagination or Media Count : 69


Abstract : Poly(ADP-ribose) polymerase (PARP) inhibition provides a promising therapeutic modality for targeting homologous recombination (HR) deficient 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 BRCA1/2-deficient cancers is through the restoration of HR. Recent studies from our laboratories (Nussenzweig and D'Andrea) indicate that deregulation of pathways that promote extensive degradation of nascent DNA strands and alternative end-joining (Alt-EJ) can render BRCA1/2-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 drives 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 chemoresistance in BRCA1/2-mutated breast cancers. During the first year of the DOD funding, we have made progress in identifying the proteins which contribute to the replication fork stability and we have identified new mechanisms of chemoresistance in BRCA2-deficient tumors.


Descriptors :   breast cancer , genes , inhibitors , chemotherapy , drug resistance , neoplasms


Subject Categories : Medicine and Medical Research
      Genetic Engineering and Molecular Biology
      Pharmacology


Distribution Statement : APPROVED FOR PUBLIC RELEASE