Determine the Impact of Novel BRCA1 Translation Start Sites on Therapy Resistance in Ovarian Cancer
Abstract
Purpose: Recently, PARP inhibitors have emerged as promising agents for the treatment of BRCA1 mutant ovarian cancers. However, similar to platinum, drug resistance is a major clinical hurdle. Scope: In this proposal, we aimed to characterize N-terminal deficient BRCA1 proteins contribution to DNA damage repair and their ability to confer resistance to ovarian cancer therapeutics, as well as identify novel small molecules that specifically kill N-terminal deficient BRCA1 protein expressing cells. Major findings: We expressed a number of BRCA1 proteins produced from downstream translation start sites that were truncated at the N-terminal region and lacked the RING domain. We show that RING deficient-BRCA1 proteins were hypomorphic, contributing to RAD51 loading, PARPi and cisplatin resistance. The mechanism we describe may not be limited to cancers with BRCA1185delAG mutations and could be relevant to multiple frameshifting 5 located BRCA1 mutations. However, mutations located after Met-297 (c.891) are unlikely to develop resistance through this mechanism, as we show that the next downstream translation start site at Met-531 (c.1593) produced a functionless protein. Additionally, we identified three new small molecules that could be developed as drugs to specifically target PARP inhibitor resistant cancers that express N-terminal deficient BRCA1 proteins.
Document Details
- Document Type
- Technical Report
- Publication Date
- Sep 01, 2017
- Accession Number
- AD1045107
Entities
People
- Neil F. Johnson