HER3介导转移性结直肠癌和胰腺癌的代谢重编程

Background: Liver metastasis occurs in ~80% of all metastatic colorectal cancer (mCRC) and metastatic pancreatic cancer (mPC), and the liver has a unique microenvironment that promotes cancer cell survival. Prior studies from our group and others have reported that the liver endothelium and hepatocytes secrete soluble factors (NRG1 and LRG1) that activate the cancer-associated HER3 signaling pathway and promote cancer growth. This study examines the impact of HER3 signaling on the metabolism of mCRC and mPC, aiming to identify a novel therapeutic approach. Methods : We performed mass spectrometry to profile the metabolic changes in mCRC and mPC tumors with/without HER3 inhibition in a syngeneic, orthotopic mouse model with hepatic injection. We also performed in vitro metabolic assays to determine the effect of HER3 ligands on the metabolism of CRC and PC. To further define the role of HER3 in metabolic reprogramming, we used siRNA silencing of HER3 and pharmacological inhibition of HER3 downstream signaling proteins to identify the key mediator(s) of HER3-induced metabolic shift. We performed in vitro synergy studies combining HER3i (Sapitinib) with oxidative phosphorylation (OXPHOS) inhibitors (metformin and ivosedinib). To further determine the synergistic efficacy in vivo , we established syngeneic, orthotopic metastases of mCRC/mPC in the liver via hepatic injection and treated the mice with HER3 and OXPHOS inhibitors. Results : We found that HER3 ligands increase cell acidification and lactate secretion (as measured by Seahorse FX and ELISA, established readouts of glycolysis) while simultaneously reducing oxygen consumption and mitochondrial membrane potential (as measured by Seahorse FX and TMRE, key indicators of oxidative phosphorylation metabolites, OXPHOS). We found that PFK2 is activated by HER3 signaling, as determined by phosphorylation, and that the HER3-AKT/RSK-PFK2 signaling axis is the key mediator of HER3-induced glycolysis. We then determined that HER3 inhibition decreased glycolysis readouts but induced an adaptive survival strategy by causing a metabolic shift towards OXPHOS. Thus, we found that simultaneous inhibition of HER3 and OXPHOS synergistically blocked the growth of cancer cells in vitro and led to an unprecedented 70% complete response in mouse models with orthotopic mCRC/mPC liver metastases. Conclusions : We identified the HER3-AKT/RSK-PFK2 axis as a promoter of glycolysis and growth in CRC/PC liver metastases. Leveraging the discovery of metabolic shifting towards OXPHOS caused by HER3 inhibition, we identified a potential therapeutic strategy of combining HER3 inhibitors and OXPHOS inhibitors for treating patients with mCRC/mPC.