GUK1 activation represents a metabolic vulnerability in lung cancer

Feb.2025 10

Introduction

GUK1 activation is a metabolic liability in lung cancer

Details

Metabolic vulnerabilities in oncogene-driven lung cancer remain poorly understood. In recent study, Jaime L. Schneider conducted a phosphoproteomic screen in anaplastic lymphoma kinase (ALK)-rearranged (“ALK+”) patient-derived cell lines and identified guanylate kinase 1 (GUK1), a key enzyme in guanosine diphosphate (GDP) synthesis, as a downstream target of ALK signaling. Their findings show that ALK directly binds to and phosphorylates GUK1 at tyrosine 74 (Y74), leading to enhanced GDP production. Spatial imaging of ALK+ tumor samples further reveals elevated phosphorylation of GUK1, which strongly correlates with increased guanine nucleotide levels in situ. Disruption of GUK1 phosphorylation reduces intracellular GDP and GTP pools, impairing MAPK signaling and Ras-GTP activation. A non-phosphorylatable GUK1 mutant (Y74F) reduces tumor cell proliferation both in vitro and in vivo. Furthermore, GUK1 phosphorylation is also regulated by other oncogenic fusion proteins in lung cancer. These findings highlight potential metabolic dependencies in oncogene-driven lung cancers, offering new avenues for targeted therapeutic strategies.

Highlight

Phosphoproteomics reveals GUK1, a GDP-synthesizing enzyme, as a target of ALK signaling.
Phosphorylation of GUK1 enhances GDP production, playing a critical role in tumor growth.
GUK1 phosphorylation influences MAPK signaling by promoting Ras-GTP activation.
In lung cancer, GUK1 activation is modulated by various oncogenic fusion proteins.

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