PU-H71 alters metabolism to suppress growth in pancreatic cancer

Pancreatic ductal adenocarcinoma (PDAC) is a deadly cancer with limited therapeutic options. Oncogenic KRAS signaling, mainly via the mitogen-activated protein kinase (MAPK) pathway, is the key driver of PDAC. To sustain its growth and resist therapy, PDAC tumors continuously reprogram their metabolic activities. To identify therapeutic agents capable of disrupting these adaptive survival activities, we performed a high-throughput drug screen of >2,000 compounds in two PDAC cell lines. This screen identified PU-H71, a selective epichaperome and heat shock protein 90 inhibitor, as a potent suppressor of PDAC viability. PU-H71 reduced short-term cell growth and impaired clonogenic survival across multiple PDAC models. Metabolomics profiling revealed that treatment with PU-H71 consistently altered intracellular amino acid levels, metabolites in key biochemical pathways, and caused a significant shift in extracellular metabolites, suggesting coordinated changes in metabolite flux and utilization. Further, treatment of PDAC cells with PU-H71 reduced the phosphorylation of mTOR-associated signaling components and suppressed the MAPK signaling pathway. Together, these findings indicate that PU-H71 disrupts PDAC survival by simultaneously perturbing metabolic programming and growth signaling networks. Our results identify PU-H71 as a promising therapeutic agent for targeting the crosstalk between metabolism and signaling programs that promote PDAC growth and therapeutic resistance.