1. Academic Validation
  2. SPRY4 inhibits and sensitizes the primary KIT mutants in gastrointestinal stromal tumors (GISTs) to imatinib

SPRY4 inhibits and sensitizes the primary KIT mutants in gastrointestinal stromal tumors (GISTs) to imatinib

  • Gastric Cancer. 2023 May 24. doi: 10.1007/s10120-023-01402-4.
Shujing Li 1 2 Sien Zhao 1 Nianhai Liang 1 Shaoting Zhang 1 Liangying Zhang 1 Liangji Zhou 3 Anbu Liu 1 Xu Cao 1 Jinhai Tian 1 Yuanyuan Yu 4 Zhaoyang Fan 1 Kun Xiao 1 Ming Wang 1 Hui Zhao 3 Ru Bai 1 Jianmin Sun 5
Affiliations

Affiliations

  • 1 NHC Key Laboratory of Metabolic Cardiovascular Diseases Research, Science and Technology Center, School of Basic Medical Sciences, Ningxia Medical University, Yinchuan, China.
  • 2 Department of Pediatrics, The General Hospital of Ningxia Medical University, Yinchuan, China.
  • 3 Key Laboratory for Regenerative Medicine, Ministry of Education, School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China.
  • 4 Department of Emergency, The General Hospital of Ningxia Medical University, Yinchuan, China.
  • 5 NHC Key Laboratory of Metabolic Cardiovascular Diseases Research, Science and Technology Center, School of Basic Medical Sciences, Ningxia Medical University, Yinchuan, China. jianmin.sun@nxmu.edu.cn.
Abstract

Background: KIT is frequently mutated in gastrointestinal stromal tumors (GISTs), and the treatment of GISTs largely relies on targeting KIT currently. In this study, we aimed to investigate the role of sprouty RTK signaling antagonist 4 (SPRY4) in GISTs and related mechanisms.

Methods: Ba/F3 cells and GIST-T1 cell were used as cell models, and mice carrying germline KIT/V558A mutation were used as animal model. Gene expression was examined by qRT-PCR and western blot. Protein association was examined by immunoprecipitation.

Results: Our study revealed that KIT increased the expression of SPRY4 in GISTs. SPRY4 was found to bind to both wild-type KIT and primary KIT mutants in GISTs, and inhibited KIT expression and activation, leading to decreased cell survival and proliferation mediated by KIT. We also observed that inhibition of SPRY4 expression in KITV558A/WT mice led to increased tumorigenesis of GISTs in vivo. Moreover, our results demonstrated that SPRY4 enhanced the inhibitory effect of imatinib on the activation of primary KIT mutants, as well as on cell proliferation and survival mediated by the primary KIT mutants. However, in contrast to this, SPRY4 did not affect the expression and activation of drug-resistant secondary KIT mutants, nor did it affect the sensitivity of secondary KIT mutants to imatinib. These findings suggested that secondary KIT mutants regulate a different downstream signaling cascade than primary KIT mutants.

Conclusions: Our results suggested that SPRY4 acts as negative feedback of primary KIT mutants in GISTs by inhibiting KIT expression and activation. It can increase the sensitivity of primary KIT mutants to imatinib. In contrast, secondary KIT mutants are resistant to the inhibition of SPRY4.

Keywords

GISTs; Imatinib; KIT; Mutation; SPRY4.

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