Sotorasib induces intestinal epithelial injury through suppression of the cAMP/PKA/CREB signaling axis

  • Biochem Pharmacol. 2026 Sep;251(Pt 1):118078. doi: 10.1016/j.bcp.2026.118078.
Jiajia Chen  1 ,  Xiaoxiao Liu  1 ,  Ruoyu Wang  1 ,  Jinjin Li  1 ,  Zhifei Xu  1 ,  Bo Yang  2 ,  Qiaojun He  3 ,  Xiaochun Yang  4 ,  Hao Yan  5 ,  Peihua Luo  6
Affiliations
  • 1. Center for Drug Safety Evaluation and Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.
  • 2. Institute of Pharmacology & Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China; School of Medicine, Hangzhou City University, Hangzhou 310015, China.
  • 3. Center for Drug Safety Evaluation and Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China; Innovation Institute for Artificial Intelligence in Medicine of Zhejiang University, Hangzhou 310018, China.
  • 4. Center for Drug Safety Evaluation and Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China; Innovation Institute for Artificial Intelligence in Medicine of Zhejiang University, Hangzhou 310018, China; Nanhu Brain-computer Interface Institute, Hangzhou 311100, China.
  • 5. Center for Drug Safety Evaluation and Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China. Electronic address: [email protected].
  • 6. Center for Drug Safety Evaluation and Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China; Innovation Institute for Artificial Intelligence in Medicine of Zhejiang University, Hangzhou 310018, China. Electronic address: [email protected].
PMID: 42144204 DOI: 10.1016/j.bcp.2026.118078
Abstract

Sotorasib, a first-in-class KRAS G12C inhibitor, has demonstrated substantial clinical efficacy in KRAS G12C-mutant malignancies but is frequently associated with gastrointestinal adverse events, the mechanisms of which remain poorly understood. In this study, we investigated the molecular basis of sotorasib-induced intestinal toxicity using complementary in vitro and an HP-β-CD-optimized in vivo model. Sotorasib treatment disrupted intestinal epithelial homeostasis by promoting Apoptosis and suppressing proliferative capacity, resulting in impaired epithelial barrier integrity. Mechanistically, sotorasib markedly suppressed intracellular cAMP signaling in intestinal epithelial cells, as evidenced by reduced protein kinase A (PKA) activity and decreased phosphorylation of the transcription factor CREB. These effects were consistently observed in IEC-6 cells and murine colonic tissues lacking the KRAS G12C mutation, indicating a KRAS-independent mechanism. Pharmacological elevation of intracellular cAMP with forskolin partially restored CREB phosphorylation, attenuated epithelial Apoptosis, enhanced proliferative activity, and improved expression of barrier-associated markers. In contrast, in NCI-H358 cells, forskolin increased CREB phosphorylation but failed to rescue sotorasib-induced growth inhibition, highlighting a pronounced cell type-dependent response to sotorasib. Collectively, our findings identify suppression of the cAMP/PKA/CREB signaling axis as a key mechanism underlying sotorasib-induced intestinal epithelial injury and provide mechanistic insight into the tissue-selective gastrointestinal toxicity of KRAS G12C-targeted therapy.

Keywords
CREB; Intestinal epithelial injury; Sotorasib; cAMP.
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