2. Academic Validation
  3. WWP1 inhibition increases SHP2 inhibitor efficacy in colorectal cancer

WWP1 inhibition increases SHP2 inhibitor efficacy in colorectal cancer

  • NPJ Precis Oncol. 2024 Jul 16;8(1):144. doi: 10.1038/s41698-024-00650-6.
Hao Fan # 1,  Xuefei Hu # 2,  Fuao Cao # 1,  Leqi Zhou # 1,  Rongbo Wen 1,  Hao Shen 2,  Yating Fu 2,  Xiaoming Zhu 1,  Hang Jia 1,  Zixuan Liu 1,  Guimin Wang 1,  Guanyu Yu 3,  Wenjun Chang 4,  Wei Zhang 5
Affiliations

Affiliations

  • 1 Department of Colorectal Surgery, Changhai Hospital, Naval Medical University, Shanghai, China.
  • 2 Department of Navy Environmental and Occupational Health, Faculty of Naval Medicine, Naval Medical University, Shanghai, China.
  • 3 Department of Colorectal Surgery, Changhai Hospital, Naval Medical University, Shanghai, China. yuguanyu0451@163.com.
  • 4 Department of Navy Environmental and Occupational Health, Faculty of Naval Medicine, Naval Medical University, Shanghai, China. cwjcwj1976@smmu.edu.cn.
  • 5 Department of Colorectal Surgery, Changhai Hospital, Naval Medical University, Shanghai, China. weizhang2000cn@163.com.
  • # Contributed equally.
PMID: 39014007 DOI: 10.1038/s41698-024-00650-6
Abstract

Protein tyrosine Phosphatase SHP2 activates Ras signaling, which is a novel target for colorectal Cancer (CRC) therapy. However, SHP2 Inhibitor monotherapy is ineffective for metastatic CRC and a combination therapy is required. In this study, we aimed to improve the antitumor efficacy of SHP2 inhibition and try to explore the resistance mechanism of SHP2 Inhibitor. Results showed that WWP1 promoted the proliferation of CRC cells. Genetic or pharmacological inhibition of WWP1 enhanced the effect of SHP2 Inhibitor in suppressing tumor growth in vitro and in vivo. WWP1 may mediate feedback reactivation of Akt signaling following SHP2 inhibition. Furthermore, nomogram models constructed with IHC expression of WWP1 and SHP2 greatly improved the accuracy of prognosis prediction for patients with CRC. Our findings indicate that WWP1 inhibitor I3C can synergize with SHP2 Inhibitor and is expected to be a new strategy for clinical trials in treating advanced CRC patients.

Figures
Products