Abstract IA010: Targeting genome instability in cancer: Translating synthetic lethal biology into the clinic

Abstract Membrane-associated tyrosine- and threonine-specific Cdc2-inhibitory kinase (PKMYT1) is a cell cycle regulatory kinase that inhibits CDK1/CyclinB activity, delaying entry into mitosis in tumor cells experiencing replication stress (RS). RS is frequently induced by genetic alterations that drive premature transition from G1 to S phase, promoting genome instability and creating a synthetic lethal (SL) relationship between these specific alterations and PKMYT1 inhibition. This relationship has been demonstrated preclinically and clinically with CCNE1 amplification as well as FBXW7 and PPP2R1A deleterious mutations. These genetic alterations are common across a range of tumors including ovarian, endometrial and colorectal cancers. On this basis, we developed lunresertib (RP-6306), a first-in-class, potent and selective oral PKMYT1 inhibitor currently being investigated in phase I clinical trials (NCT04855656, NCT05147272, NCT05147350). Here we discuss the translation of pre-clinical data to the clinical setting as both monotherapy and mechanistic combinations approaches. Citation Format: Michael Zinda. Targeting genome instability in cancer: Translating synthetic lethal biology into the clinic abstract. In: Proceedings of the AACR Special Conference in Cancer Research: Expanding and Translating Cancer Synthetic Vulnerabilities; 2024 Jun 10-13; Montreal, Quebec, Canada. Philadelphia (PA): AACR; Mol Cancer Ther 2024;23(6 Suppl):Abstract nr IA010.