Zhu Guangrong, Shi Jun, Zhang Shaoting, Guo Yue, Huang Ling, Zhao Hui, Jiang Yideng, Sun Jianmin
1School of Basic Medical Sciences, Ningxia Medical University, No. 1160 Shengli Street, Yinchuan, 750004 China.
2Key Laboratory for Regenerative Medicine, Ministry of Education, School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, Hong Kong SAR, China.
Cell Biosci. 2020 Feb 12;10:16. doi: 10.1186/s13578-020-0377-9. eCollection 2020.
KIT mutations are the predominant driver mutations in gastrointestinal stromal tumors (GISTs), and targeted therapy against KIT has improved treatment outcome dramatically. However, gaining secondary mutation of KIT confers drug resistance of GISTs leading to treatment failure.
In this study, we found that secondary mutation of KIT dramatically increases the ligand-independent activation of the receptor and their resistance to the often used KIT inhibitor Imatinib in the treatment of GISTs. PI3 kinase plays essential roles in the cell transformation mediated by the primary mutation of KIT. We found that loss of PI3 kinase association, but not the inhibition of the lipid kinase activity of PI3 kinase, inhibits the ligand-independent activation of secondary mutations of KIT, and increases their sensitivity to Imatinib, and loss of PI3 kinase association inhibits secondary mutations of KIT mediated cell survival and proliferation in vitro. The in vivo assay further showed that the growth of tumors carrying secondary mutations of KIT is more sensitive to Imatinib when PI3 kinase association is blocked while inhibition of the lipid kinase activity of PI3 kinase cannot inhibit tumor growth, indicating that PI3 kinase is important for the drug resistance of secondary mutation of KIT independent of the lipid kinase activity of PI3 kinase.
Our results suggested that PI3 kinase is necessary for the ligand-independent activation of secondary mutations of KIT, and loss of PI3 kinase association improves the sensitivity of secondary mutations to the targeted therapy independent of the lipid kinase activity of PI3 kinase.
KIT突变是胃肠道间质瘤（GISTs）的主要驱动突变，针对KIT的靶向治疗显著改善了治疗效果。然而，获得KIT的二次突变会导致GISTs产生耐药性，从而导致治疗失败。
在本研究中，我们发现KIT的二次突变显著增加了受体的非配体依赖性激活及其在GISTs治疗中对常用KIT抑制剂伊马替尼的耐药性。PI3激酶在由KIT的原发性突变介导的细胞转化中起重要作用。我们发现PI3激酶结合的丧失，而非PI3激酶脂质激酶活性的抑制，可抑制KIT二次突变的非配体依赖性激活，并增加其对伊马替尼的敏感性，且PI3激酶结合的丧失可在体外抑制KIT二次突变介导的细胞存活和增殖。体内试验进一步表明，当PI3激酶结合被阻断时，携带KIT二次突变的肿瘤生长对伊马替尼更敏感，而抑制PI3激酶的脂质激酶活性则不能抑制肿瘤生长，这表明PI3激酶对KIT二次突变的耐药性很重要，且不依赖于PI3激酶的脂质激酶活性。
我们的结果表明，PI3激酶对于KIT二次突变的非配体依赖性激活是必需的，且PI3激酶结合的丧失可提高二次突变对靶向治疗的敏感性，且不依赖于PI3激酶的脂质激酶活性。
