Developmental Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065.
Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065.
Proc Natl Acad Sci U S A. 2017 Oct 3;114(40):E8448-E8457. doi: 10.1073/pnas.1711449114. Epub 2017 Sep 18.
Gastrointestinal stromal tumors (GISTs) predominantly harbor activating mutations in the receptor tyrosine kinase KIT. To genetically dissect in vivo the requirement of different signal transduction pathways emanating from KIT for tumorigenesis, the oncogenic mutation was combined with point mutations abrogating specific phosphorylation sites on KIT. Compared with single-mutant mice, double-mutant knock-in mice lacking the SRC family kinase-binding site on KIT (pY567) exhibited attenuated MAPK signaling and tumor growth. Surprisingly, abrogation of the PI3K-binding site (pY719) in mice prevented GIST development, although the interstitial cells of Cajal (ICC), the cells of origin of GIST, were normal. Pharmacologic inhibition of the PI3K pathway in tumor-bearing mice with the dual PI3K/mTOR inhibitor voxtalisib, the pan-PI3K inhibitor pilaralisib, and the PI3K-alpha-restricted inhibitor alpelisib each diminished tumor proliferation. The addition of the MEK inhibitor PD-325901 or binimetinib further decreased downstream KIT signaling. Moreover, combining PI3K and MEK inhibition was effective against imatinib-resistant tumors.
胃肠道间质肿瘤（GISTs）主要携带有受体酪氨酸激酶 KIT 的激活突变。为了从遗传学上解析 KIT 衍生的不同信号转导途径在肿瘤发生中的作用，我们将致癌突变与消除 KIT 上特定磷酸化位点的点突变相结合。与单突变小鼠相比，缺乏 KIT 上 SRC 家族激酶结合位点（pY567）的双突变 敲入小鼠表现出减弱的 MAPK 信号和肿瘤生长。令人惊讶的是，在 小鼠中消除 PI3K 结合位点（pY719）虽然阻断了 GIST 的发展，但 ICC（GIST 的起源细胞）仍然正常。用双重 PI3K/mTOR 抑制剂 voxtalisib、泛 PI3K 抑制剂 pilaralisib 和 PI3K-alpha 受限抑制剂 alpelisib 抑制携带肿瘤的 小鼠中的 PI3K 通路，每种药物都能减少肿瘤增殖。添加 MEK 抑制剂 PD-325901 或 binimetinib 进一步降低了下游 KIT 信号。此外，PI3K 和 MEK 抑制的联合治疗对伊马替尼耐药的 肿瘤有效。
