Abstract 3963: Tumor-intrinsic impact of PIP4K2C degradation drives preclinical efficacy in colorectal cancer

Abstract Phosphatidylinositol 5-phosphate 4-kinase, type II, gamma (PIP4K2C) is a lipid kinase with critical roles in vesicular trafficking, autophagy-dependent catabolism and modulation of the immune system. PIP4K2 kinases regulate membrane localization and clustering of PI(4, 5)P2 and thus govern multiple aspects of receptor trafficking and signaling at the plasma and vesicular membranes, independently of their catalytic function (Wang et al.). Cancer cells maintain their fitness by developing survival adaptations that foster escape from intrinsic and extrinsic mechanisms of cell death in conditions of stress. Through its ability to modulate membrane lipid dynamics, PIP4K2C plays an important role in cancer fitness and has the potential to modulate key signaling pathways and cellular responses to exogenous and endogenous stress, in turn increasing the immunogenicity of the tumor. As germline PIP4K2C knockout mice develop subclinical autoinflammatory signs with age (Shim et al.), systemic modulation of PIP4K2C both enhances anti-tumor immunity and disrupts cancer cell fitness, both impacts synergizing to reduce tumor growth in cancer patients. Achieving potent targeting of PIP4K2C while sparing other family members or other lipid kinases has so far precluded the exploration of its potential as a therapeutic target. LRK-A was developed as a bifunctional degrader of PIP4K2C causing rapid and exclusive degradation of PIP4K2C in vivo and in vitro. Degradation of PIP4K2C in tumors leads to modulation of key pro-tumorigenic pathways and upregulation of immune activating cytokines, chemokines, and stress-associated receptors. Subsequently, tumors are more susceptible to immune cell killing by NK cells and phagocytosis by dendritic cells. Concurrently, PIP4K2C degradation in phagocytes increases PIP2 production and mediates an increased uptake of dead tumor material, enabling a synergistic, dose-dependent amplification of the immune response to cancer. Dosing of LRK-A as a single agent significantly reduces tumor growth including full regressions in a mouse syngeneic model of colorectal cancer. We further demonstrate that treatment of human primary spheroids derived from tumor resections of MSS-CRC patients leads to increased tumor cytotoxicity and upregulation of key immune activation markers. Collectively, our results show that PIP4K2C is a novel cancer fitness target at the critical convergence of tumor-intrinsic and tumor-immune pathways, and which can be specifically and effectively targeted in vivo using a bifunctional degrader. The reduced tumor growth we observed both in vivo in mice and ex vivo in human MSS-CRC patient samples upon targeting PIP4K2C alone suggests that PIP4K2C is a highly promising target for therapeutic intervention. Further explorations are ongoing to enable the development of PIP4K2C-targeted therapeutic strategies. Wang DG et al. Cell Rep. 2019; Shim H et al. PNAS 2016 Citation Format: Eva d'Hennezel, Morgan O'Shea, Guosen Ye, Kristin Brown, Andrew Good, Melvyn Chow, Julie Arnold, Lilly Ein, Vincent Giacalone, Robert Prenovitz, Sebastian Hayes, Sydney Alnemy, Erica Dube, oluwatimileyin A. Adigun, Kirti Khardenavis, Alyssa Martin, Michael Perricone, Krista Goodman, Emily Corse, Catherine Sabatos-Peyton. Tumor-intrinsic impact of PIP4K2C degradation drives preclinical efficacy in colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3963.