Suppression of the HBP Function Increases Pancreatic Cancer Cell Sensitivity to a Pan-RAS Inhibitor

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a leading cause of cancer-related death and the search for a resolutive therapy is still a challenge. Since KRAS is commonly mutated in PDAC and is one of the main drivers of PDAC progression, its inhibition should be a key strategy for treatment, especially considering the recent development of specific KRAS inhibitors. Nevertheless, the effects of KRAS inhibition can be increased through the co-inhibition of other nodes important for cancer development. One of them could be the hexosamine biosynthetic pathway (HBP), whose enhancement is considered fundamental for PDAC. Here, we demonstrate that PDAC cells expressing oncogenic KRAS, owing to an increase in the HBP flux, become strongly reliant on HBP for both proliferation and survival. In particular, upon treatment with two different compounds, 2-deoxyglucose and FR054, inhibiting both HBP and protein N-glycosylation, these cells undergo apoptosis significantly more than PDAC cells expressing wild-type KRAS. Importantly, we also show that the combined treatment between FR054 and the pan-RAS inhibitor BI-2852 has an additive negative effect on cell proliferation and survival by means of the suppression of both Akt activity and cyclin D1 expression. Thus, co-inhibition of HBP and oncogenic RAS may represent a novel therapy for PDAC patients.

Targeting PGM3 as a Novel Therapeutic Strategy in KRAS/LKB1 Co-Mutant Lung Cancer

“…Recent studies reported that FR054, a specific inhibitor of PGM3, has an anti-cancer effect in breast and pancreatic cancer models, both in vitro and in vivo without having severe adverse effects [ 26 , 27 , 28 ]. Before examining the anti-cancer effect of FR054 in NSCLC, we aimed to confirm whether FR054 effectively inhibits PGM3 activity.…”

PGM3 regulates beta-catenin activity to promote colorectal cancer cell progression

“…12 Similarly, suppression of the PGM3 function by a specific inhibitor FR054 improves the susceptibility of pancreatic cancer cells to a pan-RAS inhibitor. 14 PGM3 inhibition through FR054 induces breast cancer growth arrest and apoptosis. 15 Meanwhile, PGM3 expression is elevated in prostate cancer samples, suggesting a pro-oncogenic role for PGM3.…”

“…Previously, the pro-tumorigenic functions of PGM3 have been reported in cancers of breast, uterine, prostate, and pancreas. 12–15 PGM3 was significantly upregulated in CRC according to The Cancer Genome Atlas (TCGA) database. However, the biological function of PGM3 in colon cancer is still unclear.…”

Oncogenic KRAS blockade therapy: renewed enthusiasm and persistent challenges

“…Early preclinical studies confirmed its activity in blocking the KRAS pathway in NSCLC cells [180]. Using FR054 to inhibit glycosylation reactions further enhances the anticancer activity of BI-2852 against PDAC cells [181], supporting that the hexosamine biosynthesis pathway is a potential target for the treatment of KRAS-mutant cancers [182].…”