Severe metabolic alterations in liver cancer lead to ERK pathway activation and drug resistance

Abstract

Background: The extracellular signal-regulated kinase (ERK) pathway regulates cell growth, and is hyper-activated and associated with drug resistance in hepatocellular carcinoma (HCC). Metabolic pathways are profoundly dysregulated in HCC. Whether an altered metabolic state is linked to activated ERK pathway and drug response in HCC is unaddressed. Methods: We deprived HCC cells of glutamine to induce metabolic alterations and performed various assays, including metabolomics (with 13 C-glucose isotope tracing), microarray analysis, and cell proliferation assays. Glutamine-deprived cells were also treated with kinase inhibitors (e.g. Sorafenib, Erlotinib, U0126 amongst other MEK inhibitors). We performed bioinformatics analysis and stratification of HCC tumour microarrays to determine upregulated ERK gene signatures in patients. Findings: In a subset of HCC cells, the withdrawal of glutamine triggers a severe metabolic alteration and ERK phosphorylation (pERK). This is accompanied by resistance to the anti-proliferative effect of kinase inhibitors, despite pERK inhibition. High intracellular serine is a consistent feature of an altered metabolic state and contributes to pERK induction and the kinase inhibitor resistance. Blocking the ERK pathway facilitates cell proliferation by reprogramming metabolism, notably enhancing aerobic glycolysis. We have identified 24 highly expressed ERK gene signatures that their combined expression strongly indicates a dysregulated metabolic gene network in human HCC tissues. Interpretation: A severely compromised metabolism lead to ERK pathway induction, and primes some HCC cells to pro-survival phenotypes upon ERK pathway blockade. Our findings offer novel insights for understanding, predicting and overcoming drug resistance in liver cancer patients.

<p>Effects of LRP1B Regulated by HSF1 on Lipid Metabolism in Hepatocellular Carcinoma</p>

“…9,10,37 Notably, metabolic alteration is being regarded as a key hallmark of liver cancer but still remains unclear in HCC. 10,38 Previous well-studied metabolic alterations in HCC are mainly glucose, glutamine and methionine metabolism, [39][40][41] less attention has been paid to lipid metabolism features of HCC. As obesity-and NAFLD-related HCC cases increase in China, it is urgent to exploit the patterns and influences of lipid metabolism in HCC.…”

Linking Serine/Glycine Metabolism to Radiotherapy Resistance

“…This data indicates that the inhibition of PHGDH might be a promising strategy to overcome the acquired erlotinib resistance in LUAD [ 63 ]. In hepatocellular carcinoma (HCC), high intracellular serine has been identified as a common metabolic feature of kinase inhibitor resistance to sorafenib, erlotinib, U0126, among other MEK inhibitors, being an important contributor of activation of the MAPK pathway via ERK phosphorylation upon glutamine withdrawal [ 64 , 65 ].…”

Multi-dimensional analyses identify genes of high priority for pancreatic cancer research

“…5k, Extended Data Fig. 5c-d), which we previously observed is an indicator of nutrient deprivation and suppressed proliferation 26 . In both a human cell line subcutaneous xenograft model with TU8902 cell line, and in immunocompetent orthotopic mouse model with oncogenic Kras; Trp53 R172H/+ cells (KPC), the combination of gemcitabine and BETi BD-9136 synergistically suppressed tumor growth (Fig.…”