Potent and Selective PTDSS1 Inhibitors Induce Collateral Lethality in Cancers with PTDSS2 Deletion

Abstract Targeting collateral deletion of housekeeping genes caused by the loss of tumor suppressor genes is a potential strategy to identify context-specific, molecular-targeted therapies in cancer. In mammals, phosphatidylserine (PS) synthesis depends on two redundant PS synthetases, PTDSS1 and PTDSS2, and PTDSS2 is located at a tumor-suppressive locus, 11p15.5. Here, we sought to determine whether PTDSS2 loss would confer vulnerability to disruption of PTDSS1 function. PTDSS2 was lost in a wide range of cancer types, and PTDSS1 depletion specifically suppressed growth in PTDSS2-deficient cancer cell lines. Potent and selective PTDSS1 inhibitors were developed whose activity phenocopied the effect of PTDSS1 depletion, and in vivo treatment of PTDSS2-deleted tumors with these inhibitors led to tumor regression. Whole-transcriptome analysis revealed that inhibition of PTDSS1 in PTDSS2-depleted cells activated the endoplasmic reticulum (ER) stress response downstream of PS depletion. ER stress-mediated cell death induced by PTDSS1 inhibitors activated tumor immunity through the secretion of HMGB1 protein followed by activation of bone marrow-derived dendritic cells. PTDSS2 loss showed intratumoral heterogeneity in clinical samples, raising concerns about resistance to PTDSS1 inhibition. However, the PTDSS1 inhibitor effectively suppressed the growth of tumor containing both PTDSS2 wild-type and knockout cells in immunocompetent mice, showing potency for overcoming tumor heterogeneity by modulating the tumor immune microenvironment. Thus, these newly developed PTDSS1 inhibitors provide a therapeutic option for treating cancer with PTDSS2 loss, harnessing the synthetic lethality of PTDSS1/2. Significance: This study identifies a specific dependency on PTDSS1 for phosphatidylserine synthesis following PTDSS2 deletion and introduces novel PTDSS1 inhibitors as a therapeutic option to induce collateral lethality in cancer with PTDSS2 loss.