Effect of pharmacologic or genetic PIKFYVE inhibition in GEP-NET [CRISPR]

This study aims to elucidate the transcriptomic changes and metabolic reprogramming in gastroenteropancreatic neuroendocrine tumor (GEP-NET) cells following PIKfyve inhibition, using both genetic (CRISPR-mediated knockdown) and pharmacological (Apilimod treatment) approaches. The research focuses on the impact of PIKfyve inhibition on lipid metabolism, cholesterol homeostasis, and mTOR signaling in QGP-1, BON-1, and GOT-1 cell lines. By analyzing RNA sequencing data from these experimental conditions, we seek to identify differentially expressed genes and enriched pathways associated with PIKfyve inhibition. This investigation is part of a broader effort to develop novel combination therapies that could potentially overcome resistance to mTOR inhibitors, the current standard of care for advanced GEP-NETs. The study's findings may provide insights into the therapeutic potential of targeting PIKfyve-driven lipid metabolism in combination with mTOR inhibition, potentially offering new strategies to improve treatment efficacy and patient outcomes in GEP-NETs and other mTOR-driven cancers. Overall design: Genes were screened for essentiality in GEP-NET cancer cells after 14-days of growth using the human kinome CRISPR knockout pooled libraries (Brunello), Addgene #1000000083. Days 0 and 14 were screened using each half-pool separately, yielding 4 total screens. The half-pools containing sgRNA sets 1-4 and sets 5-8 are here labeled "A" and "B", respectively.