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Updated: Jun 13, 2025

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GUK1 activation is a metabolic liability in lung cancer

Jaime L Schneider1, Kiran Kurmi2, Yutong Dai3

  • 1Department 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.

Cell
|February 7, 2025
PubMed

Insights

Anaplastic Lymphoma Kinase (ALK) signaling in lung cancer drives guanylate kinase 1 (GUK1) phosphorylation, increasing guanosine diphosphate (GDP) synthesis. Targeting GUK1 may offer new therapeutic strategies for oncogene-driven lung cancers.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Metabolism

Background:

  • Metabolic vulnerabilities in oncogene-driven lung cancer remain largely unexplored.
  • Anaplastic Lymphoma Kinase (ALK) rearrangements are a key driver in a subset of lung cancers.

Purpose of the Study:

  • To identify metabolic targets of ALK signaling in lung cancer.
  • To investigate the role of guanylate kinase 1 (GUK1) in ALK-driven lung cancer.

Main Methods:

  • Phosphoproteomic screening in ALK-rearranged (ALK+) patient-derived cell lines.
  • Spatial imaging of ALK+ patient tumor specimens.
  • In vitro and in vivo functional assays using GUK1 variants.

Main Results:

  • Guanylate Kinase 1 (GUK1) identified as a direct target of ALK signaling.
  • ALK phosphorylates GUK1 at tyrosine 74 (Y74), enhancing guanosine diphosphate (GDP) biosynthesis.
  • GUK1 phosphorylation correlates with guanine nucleotide levels and drives tumor proliferation via MAPK signaling.

Conclusions:

  • GUK1 is a critical metabolic node regulated by ALK signaling in lung cancer.
  • Inhibition of GUK1 phosphorylation reduces tumor growth and may represent a therapeutic strategy.
  • GUK1 phosphorylation is also regulated by other oncogenic fusion proteins in lung cancer.
Keywords:
ALKGDPGUK1Ras signalinganaplastic lymphoma kinasecancer metabolismguanylate kinase 1lung cancernon-small cell lung cancertyrosine kinase inhibitor

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