Abstract 5574: Degradation of PIP4K2C by novel bivalent functional degrader LRK-A induces tumor regression in CRC
Authors: Corse Emily , Goodman Krista , O'Shea Morgan , Ye Guosen , Chow Melvyn , Arnold Julie , Giacalone Vincent , Hayes Sebastian , Dube Erica , Alnemy Sydney , Adigun Oluwatimileyin Akinrinmade , Brown Kristin , d'Hennezel Eva , Sabatos-Peyton Catherine 
Published: March 2024

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. Family members PIP4K2A and PIP4K2B are implicated in regulation of autophagy, cancer cell proliferation, and response to insulin, whereas PIP4K2C has a unique function in the immune response to cancer. Beyond the ability to convert PI5P to PI45P2, PIP4K2 kinases regulate membrane localization and clustering of PI45P2 and thus govern multiple aspects of membrane trafficking. These activities are likely to be independent of catalytic function1. The involvement of PIP4K2C in membrane lipid dynamics has the potential to broadly impact pro-tumor and immune-suppressive biology in cancer, including uptake of cancer cells by immune cells, and subsequently increase antigen processing, presentation, and T cell activation. Mice deficient in PIP4K2C develop immune cell infiltrates in tissues and increased proinflammatory cytokines in plasma2, suggesting that modulation of PIP4K2C could enhance anti-tumor immunity 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. Here, we report the discovery of the highly potent and specific PIP4K2C bifunctional degrader LRK-A, which shows rapid and exclusive degradation of PIP4K2C. We show that LRK-A can rapidly and deeply degrade PIP4K2C in primary human PBMCs and cancer cells in vitro, and with broad species cross-reactivity. The specificity of LRK-A for PIP4K2C was established using whole-cell proteomic analyses, without co-degradation of off-target proteins including SALL4 and GSPT1. In mice treated with LRK-A, we observed a dose-dependent, profound, and sustained degradation of PIP4K2C. We further demonstrate that dosing of LRK-A as a single agent significantly reduced tumor growth, including full regressions, at low doses in a mouse syngeneic model of colorectal cancer.
Collectively, our results show that PIP4K2C can be specifically and effectively targeted in vivo using a bifunctional degrader. The reduced tumor growth we observed 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.
References
1. Wang DG, Paddock MN, Lundquist MR, et al. PIP4Ks Suppress Insulin Signaling through a Catalytic-Independent Mechanism. Cell Rep. 2019;27(7):1991-2001. doi:10.1016/j.celrep.2019.04.0702. Shim H, Wu C, Ramsamooj S, et al. Deletion of the gene Pip4k2c, a novel phosphatidylinositol kinase, results in hyperactivation of the immune system. Proc Natl Acad Sci U S A. 2016;113(27):7596-7601. doi:10.1073/pnas.1600934113
Citation Format: Emily Corse, Krista Goodman, Morgan O'Shea, Guosen Ye, Melvyn Chow, Julie Arnold, Vincent Giacalone, Sebastian Hayes, Erica Dube, Sydney Alnemy, Oluwatimileyin Akinrinmade Adigun, Kristin Brown, Eva d'Hennezel, Catherine Sabatos-Peyton. Degradation of PIP4K2C by novel bivalent functional degrader LRK-A induces tumor regression in CRC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5574.