392 Mechanisms of resistance of STP938 in ovarian cancer

Objectives/Goals: Ovarian cancer is the most lethal gynecologic cancer with emergence of recurrent and resistant disease being frequent. We sought to identify novel ways to effectively kill chemotherapy-resistant forms of ovarian cancer and to prevent recurrence following curative intent with surgical and adjuvant regimens. Methods/Study Population: Our group identified CTPS1 as a novel dependency in triple negative breast cancer (TNBC) and ovarian cancer. We found CTPS1 was highly expressed in breast and ovarian tumor tissues and therapy-resistant models. We demonstrated siRNA knockdown of CTPS1 reduced proliferation in sensitive and resistant cell lines. In collaboration with Step Pharma, who developed the first CTPS1 inhibitor (STP938), we performed genome-wide CRISPR KO screens on STP938-sensitive and -resistant cells. Top synthetic lethal hits identified included TSC1, TSC2, and PPP2R2A. Synergy assays were conducted with STP938 in combination with mTOR inhibitors (Everolimus, Sirolimus, and Temsirolimus) and the PPP2R2A inhibitor LB-100 to evaluate the therapeutic benefit of combination therapies. Results/Anticipated Results: We identified CTPS1 as a novel vulnerability in many ovarian cancer cell line models, including models of chemotherapy and/or PARP inhibitor resistance. The first-in-class CTPS1 inhibitor (STP938) was shown to be a highly effective anticancer agent in sensitive and resistant forms of ovarian cancer, both in vitro and in vivo . Genome-wide CRISPR KO screens identified central components of the mTOR pathway (TSC1 and TSC2), as well as PPP2R2A, as synthetic lethal targets in the setting of STP938 exposure. We anticipate that combinatorial treatment of mTOR inhibitors and PP2R2A inhibitors with STP938 will further enhance efficacy and reduce the risk of recurrence when used in the adjuvant treatment of ovarian cancer patients. Discussion/Significance of Impact: This study will validate synthetic lethal interactions from our CRISPR screen, reveal genes that could be mutated in ovarian cancer patients that may be driving resistance to STP938, and uncover combination therapies that can be used to increase efficacy in ovarian cancer patients treated with STP938.