CTPS1 is an unexplored vulnerability in breast and ovarian cancer.

Triple negative breast cancer (TNBC) and ovarian cancer share many molecular features and are primarily treated with surgical resection and aggressive chemotherapy regimens. Unfortunately, survival rates for patients with advanced metastatic disease are poor, highlighting the need for innovative therapeutic approaches. Using the DepMap database, we first sought to identify genes that were highly expressed and more essential for proliferation/viability in TNBC cells relative to other breast cancer subtypes. Candidate genes were validated using gene-specific siRNAs in a panel of TNBC and estrogen receptor positive breast cancer cells. CTPS1 expression, and its functional significance, was further evaluated in ovarian cancer models, including chemotherapy- and PARP inhibitor-resistant cell lines. Pharmacologic inhibition was assessed using STP938, a first-in-class selective CTPS1 inhibitor, in TNBC and ovarian cancer cells as well as in ex vivo and in vivo patient-derived xenografts (PDX). Six genes (CTPS1, HUS1, PRKRA, RAD1, RAD9A, and RHOA) were identified as potential TNBC selective dependencies. Among these, CTPS1 was prioritized for further study given that it was highly expressed, further upregulated in chemotherapy- and PARP inhibitor-resistant cell lines, and resulted in the greatest anti-neoplastic effects when depleted. Knockdown of CTPS1 confirmed its selective essentiality and resulted in rapid and durable S-phase cell cycle arrest. Pharmacologic inhibition of CTPS1 with STP938 led to robust anti-neoplastic effects at nM concentrations across both chemotherapy-sensitive and -resistant TNBC and ovarian cancer cell lines. Significant anti-neoplastic activity was observed in 6 independent ex vivo ovarian cancer PDX models. Further, STP938 significantly inhibited progression of an ovarian cancer PDX model in vivo. These findings identify CTPS1 as a critical dependency in TNBC and ovarian cancer. Selective pharmacologic inhibition of CTPS1 using STP938 is a potent inhibitor of tumor cell proliferation/viability and has anti-cancer activity in patient derived ex vivo and in vivo tumor models. These findings suggest that therapeutic targeting of CTPS1 represents an alternative approach for the management of patients with advanced and aggressive forms of these diseases.