Lindsey Aubuchon

Program: Cancer Biology

Current advisor: Priyanka Verma, PhD

Undergraduate university: University of North Carolina-Wilmington, 2022

Enrollment year: 2022

Research summary
Targeting ALC1 ATPase activity as a new synthetic lethal approach for BRCA-mutant cancers

Germline mutations in BReast CAncer genes 1/2 (BRCA1/2) significantly increase lifetime risk for the development of various cancer types. Poly (ADP-ribose) polymerase inhibitors (PARPi) have been developed for the treatment of BRCA-mutant cancers; however, the emergence of resistance and severe side effects can occur with the use of these therapies. Therefore, the identification of new therapeutic targets for the treatment of BRCA-mutant cancers are desperately needed to improve treatment options for patients. Genetic depletion of Amplified in Liver Cancer 1 (ALC1) has been previously shown to hypersensitize BRCA-mutant cells to PARPi therapy. Interestingly, my preliminary experiments have shown that loss of ALC1 ATPase activity independent of PARPi leads to decreased viability of BRCA-mutant cancer cells. This highlights that targeting ALC1 ATPase activity can be a new synthetically lethal strategy for BRCA-mutant cancers. My project aims to define mechanistic insights into why ALC1 ATPase loss is synthetic lethal with BRCA-deficiency. Additionally, I will conduct a deep mutational scanning approach to identify key residues that allosterically regulate ATPase activity of ALC1. Together, these studies with provide a strong foundation to develop a new and potent therapeutic strategy for combating BRCA-mutant cancers.

Graduate publications
Ramakrishnan N, Weaver TM, Aubuchhon LN, Woldegerima A, Just T, Song K, Vindigni A, Freudenthal BD, Priyanka Verma P. 2024 Nucleolytic processing of abasic sites underlies PARP inhibitor hypersensitivity in ALC1-deficient BRCA mutant cancer cells. Nat Commun, 15(1):6343. PMCID: PMC11283519

Aubuchon LN, Verma P. 2024 Endogenous base damage as a driver of genomic instability in homologous recombination-deficient cancers. DNA repair, 141():103736