Selective PI3Kδ inhibitor TYM-3-98 suppresses AKT/mTOR/SREBP1-mediated lipogenesis and promotes ferroptosis in KRAS-mutant colorectal cancer

  • Cell Death Dis. 2024 Jul 3;15(7):474. doi: 10.1038/s41419-024-06848-7.
Ya-Nan Zheng  #  1 ,  Si-Yue Lou  #  1  2 ,  Jun Lu  1 ,  Fan-Li Zheng  1  3 ,  Yong-Mei Tang  4 ,  En-Jun Zhang  1 ,  Sun-Liang Cui  5 ,  Hua-Jun Zhao  6  7
Affiliations
  • 1. School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, China.
  • 2. Academy of Chinese Medical Sciences, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China.
  • 3. Department of Pharmacology, Zhejiang University School of Medicine, Hangzhou, People's Republic of China.
  • 4. Institute of Drug Discovery and Design, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China.
  • 5. Institute of Drug Discovery and Design, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China. [email protected].
  • 6. School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, China. [email protected].
  • 7. Academy of Chinese Medical Sciences, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China. [email protected].
  • # Contributed equally.
PMID: 38956060 DOI: 10.1038/s41419-024-06848-7
Abstract

Colorectal Cancer (CRC) is one of the most common tumors of the digestive system worldwide. KRAS mutations limit the use of anti-EGFR antibodies in combination with chemotherapy for the treatment of CRC. Therefore, novel targeted therapies are needed to overcome the KRAS-induced oncogenesis. Recent evidence suggests that inhibition of PI3K led to Ferroptosis, a nonapoptotic cell death closely related to KRAS-mutant cells. Here, we showed that a selective PI3Kδ Inhibitor TYM-3-98 can suppress the Akt/mTOR signaling and activate the Ferroptosis pathway in KRAS-mutant CRC cells in a concentration-dependent manner. This was evidenced by the lipid peroxidation, iron accumulation, and depletion of GSH. Moreover, the overexpression of the sterol regulatory element-binding protein 1 (SREBP1), a downstream transcription factor regulating lipid metabolism, conferred CRC cells greater resistance to Ferroptosis induced by TYM-3-98. In addition, the effect of TYM-3-98 was confirmed in a xenograft mouse model, which demonstrated significant tumor suppression without obvious hepatoxicity or renal toxicity. Taken together, our work demonstrated that the induction of Ferroptosis contributed to the PI3Kδ inhibitor-induced cell death via the suppression of Akt/mTOR/SREBP1-mediated lipogenesis, thus displaying a promising therapeutic effect of TYM-3-98 in CRC treatment.

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