2023 Targeted Therapies of Lung Cancer Meeting (Poster)-P1.31. GUK1 is a Novel Metabolic Liability in Oncogene-Driven Lung Cancer

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In a study conducted by Jaime L. Schneider et al., published in Nature Cancer, the authors investigated the metabolic vulnerabilities in non-small cell lung cancer (NSCLC) driven by the oncogene ALK. They aimed to identify specific metabolic dependencies in ALK-positive NSCLC and understand how metabolic reprogramming contributes to acquired resistance to ALK targeted therapies.<br /><br />Using patient-derived cell culture models and tumor specimens, the authors found that ALK-positive lung tumors have a unique metabolic signature characterized by reliance on anabolic nucleotide pathways. They identified GUK1, an enzyme responsible for GDP synthesis, as a novel metabolic target of ALK signaling. ALK was found to bind to and phosphorylate GUK1, enhancing GDP/GTP nucleotide biosynthesis. The authors demonstrated that GUK1 phosphorylation alters the activity and structure of the enzyme, promoting guanine nucleotide production. Introduction of a phosphomutant GUK1 into ALK-positive cell lines led to decreased tumor proliferation in vitro and in xenograft models.<br /><br />The authors also found that other oncogenic fusion proteins in lung cancer also regulate GUK1 phosphorylation, suggesting that GUK1 may be a metabolic liability in a broader spectrum of NSCLC. Furthermore, a subset of ALK-positive cell lines with acquired resistance to ALK targeted therapies showed increased expression and phosphorylation of GUK1, suggesting its role in mediating resistance.<br /><br />Overall, this study revealed that GUK1 is a novel metabolic vulnerability in ALK-driven lung cancers. The findings provide insights into the metabolic rewiring in ALK-positive NSCLC and highlight the potential of targeting metabolic vulnerabilities as a therapeutic approach in oncogene-driven lung cancers.

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Jaime Schneider, Massachusetts General Hospital, United States

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Speaker Jaime Schneider, Massachusetts General Hospital, United States

Topic Poster Listing

Keywords

metabolic vulnerabilities

non-small cell lung cancer

ALK oncogene

metabolic reprogramming

ALK-positive NSCLC

anabolic nucleotide pathways

GUK1 enzyme

GDP synthesis

phosphomutant GUK1

acquired resistance