Abstract B18: Mechanisms of regulation and synthetic lethal strategies against PALB2 and APRIN, two DNA double-strand break repair proteins

One typical mechanism to promote genomic instability, a hallmark of cancer, is to inactivate tumor suppressors, such as PALB2. It has recently been reported that mutations in PALB2 increase the risk of breast cancer by 8-9 fold. PALB2 was identified BRCA2 interacting protein, essential for BRCA2 anchorage to nuclear structures and for its function in double-strand break repair. Inherited mutations in PALB2 are associated with a predisposition for ovarian, breast and pancreatic cancers. The basis of the tumorigenic potential of PALB2 is thought to be related to functions in homologous recombination. Therefore, the regulation of PALB2 during the DNA damage response and the effect of cancer-causing mutation is of high interest. Two mechanisms of regulation of PALB2 will be presented. The first mechanism regulates PALB2 localization to DNA damage sites in S-phase. To date, predicting the functional consequences of PALB2 mutations has been challenging as they lead to different aggressive phenotypes. Here, we performed a structure-function analysis of PALB2 using PALB2 truncated mutants (R170fs, L531fs, Q775X and W1038X), and uncovered a second PALB2 regulation mechanism by which cancer cells could drive genomic instability. We will present these regulatory mechanisms and synthetic lethal strategies to kill PALB2 deficient cells harbouring such mutations using PARP inhibitors. These strategies also apply to APRIN, A BRCA2 interactor, which also promote double-strand break repair by homologous recombination. Citation Format: Anthony M. Couturier, Rémi Buisson, Joris Pauty, Amélie Rodrigue, Marie-Christine Caron, Yan Coulombe, Niraj Joshi, Lee Zou, Jean-Yves Masson. Mechanisms of regulation and synthetic lethal strategies against PALB2 and APRIN, two DNA double-strand break repair proteins [abstract]. In: Proceedings of the AACR Precision Medicine Series: Opportunities and Challenges of Exploiting Synthetic Lethality in Cancer; Jan 4-7, 2017; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2017;16(10 Suppl):Abstract nr B18.