Mutant KRAS downregulates the receptor for leukemia inhibitory factor (LIF) to enhance a signature of glycolysis in pancreatic cancer and lung cancer

Pancreatic cancer is characterized by aberrant activity of factor STAT3, indicating a tumor-suppressive role for STAT3 oncogenic KRAS, which is mutated in 90% of pancreatic adewithin cancer cells with mutated KRAS. Finally, reflecting a nocarcinomas. Because KRAS itself is a challenging therapeutic clinically important tumor-suppressive role of LIFR, decreased target, we focused on understanding key signaling pathways LIFR expression correlates with shorter survival in pancreatic driven by KRAS as a way to reveal dependencies that are cancer patients with mutated KRAS. Similar findings were found amenable to therapeutic intervention. Analyses in primary in non–small cell lung cancers driven by mutated KRAS, suggest-human pancreatic cancers and model systems revealed that the ing that silencing LIFR is a generalized mechanism of KRAS-receptor for the cytokine leukemia inhibitory factor (LIF) is mediated cellular transformation. These results indicate that the downregulated by mutant KRAS. Furthermore, downregulation LIFR/STAT3 pathway may mediate either tumor-promoting or of the LIF receptor (LIFR) is necessary for KRAS-mediated tumor-suppressive signaling pathways depending on the genetic neoplastic transformation. We found LIFR exerts inhibitory background of tumor cells, and may play diverse roles within effects on KRAS-mediated transformation by inhibiting expresother cells in the tumor microenvironment. sion of the glucose transporter GLUT1, a key mediator of the enhanced glycolysis found in KRAS-driven malignancies. Implications: Mutant KRAS drives downregulation of the receptor Decreased LIFR expression leads to increased GLUT1 as well for LIF, thereby allowing an increase in expression of the glucose as increases in glycolysis and mitochondrial respiration. The transporter GLUT1 and increases in glycolysis and mitochondrial repression of GLUT1 by LIFR is mediated by the transcription respiration.