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

• Published in: Gastric cancer : official journal of the International Gastric Cancer Association and the Japanese Gastric Cancer Association 2023-09, Vol.26 (5), p.677-690
• Main Authors: Li, Shujing, Zhao, Sien, Liang, Nianhai, Zhang, Shaoting, Zhang, Liangying, Zhou, Liangji, Liu, Anbu, Cao, Xu, Tian, Jinhai, Yu, Yuanyuan, Fan, Zhaoyang, Xiao, Kun, Wang, Ming, Zhao, Hui, Bai, Ru, Sun, Jianmin
• Format: Article
• Language: English
• Subjects: Abdominal Surgery; Animal models; Animals; Antagonists; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Benzamides - pharmacology; Cancer Research; Cancer therapies; Cell activation; Cell culture; Cell proliferation; Cell survival; Drug resistance; Drug Resistance, Neoplasm - genetics; Gastric cancer; Gastroenterology; Gastrointestinal cancer; Gastrointestinal Neoplasms - drug therapy; Gastrointestinal Neoplasms - genetics; Gastrointestinal Neoplasms - pathology; Gastrointestinal Stromal Tumors - drug therapy; Gastrointestinal Stromal Tumors - genetics; Gastrointestinal Stromal Tumors - pathology; Gene expression; Humans; Imatinib; Imatinib Mesylate - pharmacology; Imatinib Mesylate - therapeutic use; Immunoprecipitation; Medicine; Medicine & Public Health; Mice; Mutants; Mutation; Oncology; Original Article; Piperazines - pharmacology; Protein interaction; Proto-Oncogene Proteins c-kit - genetics; Proto-Oncogene Proteins c-kit - metabolism; Pyrimidines - pharmacology; Pyrimidines - therapeutic use; Sarcoma; Stomach Neoplasms; Surgical Oncology; Tumorigenesis
• ISSN: 1436-3291; 1436-3305
• DOI: 10.1007/s10120-023-01402-4

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 KIT V558A/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.