{
  "abstract": "Background Cancer cells maintain their fitness by developing survival adaptations that foster escape from intrinsic and extrinsic mechanisms of cell death in conditions of stress.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. PIP4K2C regulates local pools of PI(4,5)P2 through a catalytic-independent mechanism and is co-opted by cancer cells to increase their fitness by evading immune surveillance and adapting to stress.Methods 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.Results LRK-4189-mediated degradation of PIP4K2C leads to intrinsic cell death and activates type-1 immunity, triggering immune-mediated tumor killing in otherwise immune-inert MSS CRC cells. Subsequently, tumors are more susceptible to immune cell killing by NK cells and phagocytosis by dendritic cellsConclusions 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.LRK-4189 is currently in IND-enabling studies and will enter clinical trials in the fall of 2025.Ethics Approval All human material were procured and studied, and animal studies were conducted at CRO under the required ethical standards and board approval.",
  "authors": [
    {
      "affiliations": [
        "Larkspur Biosciences, Cambridge, MA, USA"
      ],
      "name": "Eva D’Hennezel"
    },
    {
      "affiliations": [
        "Larkspur Biosciences, Cambridge, MA, USA"
      ],
      "name": "Krista Goodman"
    },
    {
      "affiliations": [
        "Larkspur Biosciences, Cambridge, MA, USA"
      ],
      "name": "Morgan O’Shea"
    },
    {
      "affiliations": [
        "Larkspur Biosciences, Cambridge, MA, USA"
      ],
      "name": "Guosen Ye"
    },
    {
      "affiliations": [
        "Larkspur Biosciences, Cambridge, MA, USA"
      ],
      "name": "Melvyn Chow"
    },
    {
      "affiliations": [
        "Larkspur Biosciences, Cambridge, MA, USA"
      ],
      "name": "Sydney Alnemy"
    },
    {
      "affiliations": [
        "Larkspur Biosciences, Cambridge, MA, USA"
      ],
      "name": "Pradeep Kota"
    },
    {
      "affiliations": [
        "Larkspur Biosciences, Cambridge, MA, USA"
      ],
      "name": "Julie Arnold"
    },
    {
      "affiliations": [
        "Larkspur Biosciences, Cambridge, MA, USA"
      ],
      "name": "Lilly Ein"
    },
    {
      "affiliations": [
        "Larkspur Biosciences, Cambridge, MA, USA"
      ],
      "name": "Erica Dube"
    },
    {
      "affiliations": [
        "Larkspur Biosciences, Cambridge, MA, USA"
      ],
      "name": "Emily Corse"
    },
    {
      "affiliations": [
        "Xsphera Biosciences, Cambridge, MA, USA"
      ],
      "name": "Alyssa Martin"
    },
    {
      "affiliations": [
        "Xsphera Biosciences, Cambridge, MA, USA"
      ],
      "name": "Michael A Perricone"
    },
    {
      "affiliations": [
        "Larkspur Biosciences, Cambridge, MA, USA"
      ],
      "name": "Catherine Sabatos-Peyton"
    }
  ],
  "title": "1281 LRK-4189, a first-in-class degrader of the lipid kinase PIP4K2C for the treatment of microsatellite stable (MSS) colorectal carcinoma",
  "uid": "edad4df0-90b8-5b03-b32a-5daa4af3b8c7"
}