Sotorasib inhibits ubiquitination degradation of TXNIP and suppresses glucose metabolism in KRASG12C mutant bladder cancer.

Abstract

Bladder cancer is the most common malignant tumor of the urinary system. Currently, treatment strategies for bladder cancer remain limited, highlighting the urgent need to explore novel therapeutic approaches. Sotorasib, the first successful small molecule drug targeting KRAS, has been approved for treating non-small cell lung cancer (NSCLC), but it has not yet been studied in bladder cancer. Additionally, glucose metabolism-related proteins, such as GLUT1, PKM2, and LDHA are highly expressed in most bladder cancer cell lines, promoting tumor progression. KRAS^G12D mutant cells exhibit enhanced glucose uptake and glycolysis. However, little is known about whether KRAS^G12C mutant cells exhibit enhanced glucose metabolism. Various techniques, including glucose and lactate analysis, Seahorse assay, western blot, qRT-PCR, and immunofluorescence, were used to investigate whether Sotorasib can inhibit glucose metabolism in bladder cancer cells. The results demonstrated that Sotorasib significantly inhibited glucose metabolism in KRAS^G12C mutant bladder cancer, both in vitro and in vivo, but not in wild-type bladder cancer. Furthermore, Sotorasib's inhibition of glucose metabolism was associated with suppressing the degradation of thioredoxin-interacting protein (TXNIP), a negative regulator of glucose metabolism. Additionally, Sotorasib increased TXNIP expression by regulating the RAS/RAF/ERK axis. This study uncovers the mechanism by which Sotorasib inhibits glucose metabolism in KRAS^G12C mutant bladder cancer cells and suggests a potential therapeutic benefit for the treatment of KRAS^G12C mutant bladder cancer.