2024 Hot Topic in Basic & Translational Science: Tolerance & Resistance to Targeted Therapy in NSCLC - Posters-PP01.01: Oncogenic Signaling is Rewired to Support Nucleotide Metabolism in Acquired Resistance to Targeted Therapies in NSCLC

PP01.01: Oncogenic Signaling is Rewired to Support Nucleotide Metabolism in Acquired Resistance to Targeted Therapies in NSCLC

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This study examines how oncogenic signaling in non-small cell lung cancer (NSCLC) adapts to foster resistance against targeted therapies, focusing on nucleotide metabolism. Specifically, it centers on fusion-positive lung cancers that often develop resistance to tyrosine kinase inhibitors (TKIs), a common treatment. Research reveals that nucleotide metabolism, especially guanine nucleotide biosynthesis via GUK1 (Guanylate Kinase 1), is crucial for cancer progression and resistance mechanisms.<br /><br />The study utilized patient-derived cell lines to understand how GUK1 is regulated during TKI resistance. Resistant cells were found to maintain guanine nucleotide production independent of ALK signaling, a key oncogene in driving such cancers. GUK1 expression and its active, phosphorylated form (pGUK1) increased significantly in TKI-resistant cells, implicating GUK1 as a potential driver of resistance. Genetic experiments demonstrated that disrupting GUK1 activity affected tumor growth, underscoring its role in oncogenic processes.<br /><br />A pivotal finding was the identification of c-MET, another oncogene, as a regulator of GUK1 activation in TKI-resistant scenarios. This shift from ALK to MET highlights how oncogenic signaling can be rewired in resistant cancers. Phosphotyrosine-enriched proteomic analyses pinpointed several kinases and phosphatases that could mediate this regulation.<br /><br />The research underscores the need for new therapeutic strategies targeting metabolic pathways like those involving GUK1 to overcome resistance in fusion-positive NSCLC. Future efforts will focus on validating these kinases/phosphatases, testing GUK1 inhibitors, and exploring the broader role of metabolic reprogramming in lung cancer treatment resistance. This work could lead to novel biomarkers and treatment paradigms for combating TKI-resistant lung cancer.

Asset Subtitle

Jaime Schneider

Keywords

NSCLC

oncogenic signaling

nucleotide metabolism

tyrosine kinase inhibitors

GUK1

TKI resistance

c-MET

fusion-positive lung cancer

metabolic pathways

biomarkers