Understanding Drug Resistance in BRCA1-Associated Cancer Therapy
Abstract
Loss of BRCA1 function leads to breast and ovarian cancers in women. BRCA1-associated breast tumors tend to be triple-negative and therefore lack target therapies. In recent years, PARP inhibitors and platinum drugs have emerged to become promising cancer therapy for BRCA1-associated breast and ovarian cancers. The PARP inhibitors and platinum drugs selectively kill BRCA1-deficient cancer cells because these drugs generate a large quantity of DNA damage in tumor cells when loss of BRCA1 impairs DNA double-strand-break (DSB) repair function. A large amount of unrepaired DSBs in turn triggers programmed cell death and therefore effectively eliminates BRCA1-deficient cancer cells. However, therapies that target DNA repair deficiency in breast cancer still face the challenge of de novo and acquired therapeutic resistance. This is an issue of increasing clinical importance as more and more cancer patients undergo PARP inhibitor treatment. Some drug resistance results from certain secondary mutations in the BRCA1 gene that restore the normal function of BRCA1 protein. Other drug resistance is caused by mutations in certain proteins in the DNA repair pathway that bypass the requirement of BRCA1 in DSB repair. These two classes of secondary mutations both occur in a random fashion and the ensuing drug resistance is therefore difficult to predict. In this application, we will test a novel pathway that leads to resistance to PARP inhibitors and platinum drugs in a predicted manner. We propose that deficient BRCA1 significantly and specifically elevates the mutation rate at the FBXO44 locus, which encodes a protein that triggers BRCA1 degradation. Therefore, BRCA1 mutation-associated loss of FBXO44 leads to higher BRCA1 protein level due to increased protein stability. This in turn restores HR function for BRCA1-deficient tumor cells. This intrinsic functional loop between BRCA1 and FBXO44 is expected to mainly modulate drug sensitivity of tumor cells carrying BRCA1 missense mutations or small deletions. We will test this hypothesis using BRCA1-deficient cells from both mouse models and human clinical specimens. Understanding distinct pathways leading to PARP inhibition and platinum drug resistance by different BRCA1 mutations is key to precision medicine aimed at effective treatment of BRCA1-associated breast cancers. In addition, understanding the predicted resistance pathway offers new potential targets for therapeutic manipulation.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Aug 07, 2017
- Source ID
- W81XWH1710007
Entities
People
- Yanfen Hu
Organizations
- United States Army
- University of Texas Health Science Center at San Antonio