Research Abstract

Over the last two decades, translational research and drug discovery efforts have enabled the molecular stratification of lung cancers based on the presence of oncogenic drivers and spawned the development of targeted therapies. While genotype-directed therapy has revolutionized lung cancer treatments for patients, disease relapse is inevitable. Thus, the development of new strategies for treatment-refractory disease is a major unmet clinical need. While dysregulated metabolism is one of the most recognizable features of cancer, metabolic vulnerabilities have not been explored in the context of specific onco-genotypes and the contribution of metabolic reprogramming to the development of acquired resistance to targeted therapies is unknown. To identify metabolic vulnerabilities in distinct molecular subsets of lung cancer, we performed phosphoproteomics in anaplastic lymphoma kinase (ALK)-rearranged (“ALK+”) patient-derived lung cancer cells and identified guanylate kinase 1 (GUK1), a GDP-synthesizing enzyme, as a novel target of oncogenic signaling in lung cancer. This is the first identification of a metabolic target that controls nucleotide synthesis that is directly regulated by oncogenic fusion proteins. We provide evidence that different tyrosine kinase fusion proteins in lung cancer modulate nucleotide levels through GUK1 phosphorylation and activation. We demonstrate that modulation of metabolic signaling is sufficient to control oncogenic effects of the ALK fusion protein and that GUK1 modulation alters cellular GTP levels and MAPK signaling through Ras-GTP loading. This places GUK1 and nucleotide metabolism upstream of Ras regulation, which is a novel paradigm. In summary, these findings pave the way for the development of new therapeutic approaches by exploiting metabolic dependencies in oncogene-driven lung cancers.