SYNTHETIC LETHALITY TRIGGERED BY COMBINING OLAPARIB WITH BRCA2-RAD51 DISRUPTORS

Andrea Cavalli

University of Bologna and Italian Istitute of Tecnology, Italy

Abstract

Olaparib is the first PARP inhibitor approved by FDA in 2014 for BRCA mutation-positive ovarian cancer, and represents a successful example of the concept of synthetic lethality applied to the development of innovative anticancer agents [1-3]. Despite the undeniable benefit in BRCAless tumors, PARP inhibitors suffer from lack of efficacy in tumors with active homologous recombination (HR). Rad51 is a key recombinase of HR process. Rad51 repairs DNA double-strand breaks (DSBs), and it is recruited to DSBs site through interaction with tumor suppressor protein BRCA2 [4]. Disrupting the protein-protein interaction between Rad51 and BRCA2 could have a major impact on the survival of a cancer cell.

In the present talk, we discuss the possibility to achieve fully-small-molecule-induced synthetic lethality by combining Olaparib with a BRCA2-Rad51 disruptor identified through a lead discovery campaign. We investigated whether the new molecule could block the repair of DNA damage caused by Cisplatin in BxPC3 pancreas adenocarcinoma cell lines. Further tests were then undertaken to demonstrate the ability of the new compound to increase the response to Olaparib in cells expressing a functional BRCA2/Rad51 signaling pathway (BxPC-3), while no synergic effects were observed in Capan-1, pancreas adenocarcinoma cells lacking a functional BRCA2 protein.

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