About 4%-6% of lung adenocarcinomas, and a third of those diagnosed in people under 40 years of age, are driven by the anaplastic lymphoma kinase (ALK) gene fusion product. A continuously activated enzyme, ALK drives cancer cell proliferation through intracellular signaling mediated by Ras and its downstream effector MAP kinase. Lung cancers bearing this and analogous driver mutations are treated with tyrosine kinase inhibitors. But little was known about how the many metabolic adaptations of cancer cells contribute to sensitivity or resistance to such therapies. Researchers led by Ludwig Harvard’s Marcia Haigis took a proteomics-based approach to address this question and identified GUK1, an enzyme that synthesizes GDP, as a metabolic vulnerability in patient-derived ALK+ cell lines. They reported in a February publication in Cell that ALK binds and phosphorylates GUK1 at tyrosine 74 (Y74) to boost GDP synthesis and amplify signaling by Ras and MAP kinase. Mutating that tyrosine (Y74F) reduces GDP and GTP pools in cells, inhibits Ras signaling—which depends on GTP—and MAP kinase activation, suppressing tumor cell proliferation in cultures and in mice. This suggests that inhibiting GUK1 activation could help treat ALK+ adenocarcinomas. Notably, Marcia and colleagues find that other oncogenic mutations in lung cancer also regulate GUK1, suggesting its activation could be a more general—and equally targetable—metabolic dependency of lung cancers.
GUK1 activation is a metabolic liability in lung cancer
Cell, 2025 February 6