GUK1 activation is a metabolic liability in lung cancer

  • Cell. 2025 Jan 28:S0092-8674(25)00093-5. doi: 10.1016/j.cell.2025.01.024.
Jaime L Schneider  1 ,  Kiran Kurmi  2 ,  Yutong Dai  3 ,  Ishita Dhiman  2 ,  Shakchhi Joshi  2 ,  Brandon M Gassaway  2 ,  Christian W Johnson  4 ,  Nicole Jones  2 ,  Zongyu Li  2 ,  Christian P Joschko  2 ,  Toshio Fujino  5 ,  Joao A Paulo  2 ,  Satoshi Yoda  5 ,  Gerard Baquer  6 ,  Daniela Ruiz  6 ,  Sylwia A Stopka  6 ,  Liam Kelley  2 ,  Andrew Do  5 ,  Mari Mino-Kenudson  7 ,  Lecia V Sequist  5 ,  Jessica J Lin  5 ,  Nathalie Y R Agar  6 ,  Steven P Gygi  2 ,  Kevin M Haigis  4 ,  Aaron N Hata  5 ,  Marcia C Haigis  8
Affiliations
  • 1. Department of Cell Biology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA; Massachusetts General Hospital Cancer Center and Department of Medicine, Harvard Medical School, Boston, MA, USA. Electronic address: [email protected].
  • 2. Department of Cell Biology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA.
  • 3. Department of Cell Biology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA; Department of Chemistry and Chemical Biology, Harvard University, Boston, MA, USA.
  • 4. Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA.
  • 5. Massachusetts General Hospital Cancer Center and Department of Medicine, Harvard Medical School, Boston, MA, USA.
  • 6. Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
  • 7. Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
  • 8. Department of Cell Biology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA. Electronic address: [email protected].
PMID: 39919745 DOI: 10.1016/j.cell.2025.01.024
Abstract

Little is known about metabolic vulnerabilities in oncogene-driven lung Cancer. Here, we perform a phosphoproteomic screen in anaplastic lymphoma kinase (ALK)-rearranged ("ALK+") patient-derived cell lines and identify guanylate kinase 1 (GUK1), a guanosine diphosphate (GDP)-synthesizing enzyme, as a target of ALK signaling in lung Cancer. We demonstrate that ALK binds to and phosphorylates GUK1 at tyrosine 74 (Y74), resulting in increased GDP biosynthesis. Spatial imaging of ALK+ patient tumor specimens shows enhanced phosphorylation of GUK1 that significantly correlates with guanine nucleotides in situ. Abrogation of GUK1 phosphorylation reduces intracellular GDP and guanosine triphosphate (GTP) pools and decreases mitogen-activated protein kinase (MAPK) signaling and Ras-GTP loading. A GUK1 variant that cannot be phosphorylated (Y74F) decreases tumor proliferation in vitro and in vivo. Beyond ALK, Other oncogenic fusion proteins in lung Cancer also regulate GUK1 phosphorylation. These studies may pave the way for the development of new therapeutic approaches by exploiting metabolic dependencies in oncogene-driven lung cancers.

Keywords
ALK; GDP; GUK1; Ras signaling; anaplastic lymphoma kinase; cancer metabolism; guanylate kinase 1; lung cancer; non-small cell lung cancer; tyrosine kinase inhibitor.
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