Canine histiocytic sarcoma cell lines with SHP2 p.Glu76Gln or p.Glu76Ala mutations are sensitive to allosteric SHP2 inhibitor SHP099.
Canine histiocytic sarcoma cell lines with SHP2 p.Glu76Gln or p.Glu76Ala mutations are sensitive to allosteric SHP2 inhibitor SHP099.
复制标题
具有 SHP2 p.Glu76Gln 或 p.Glu76Ala 突变的犬组织细胞肉瘤细胞系对变构 SHP2 抑制剂 SHP099 敏感。
DOI：
10.1111/vco.12524
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发表时间：
2019
影响因子：
2.1
通讯作者：
Bonkobara M.
中科院分区：
文献类型：
--
作者：
Tani H;Kurita S;Miyamoto R;Ochiai K;Tamura K;Bonkobara M.
一些犬组织细胞肉瘤(HS)在由PTPN11编码的src同源两个含有结构域的磷酸酶2(Shp2)中带有激活突变。SHP099是SHP2的变构抑制剂，它以折叠的、自动抑制的构象稳定SHP2。在这里，我们检测了SHP2在五个犬HS细胞系中的表达和突变状态，并评价了SHP099对这些细胞系的生长抑制特性。所有5个犬HS细胞系都表达SHP2，其中3个系分别在PTPN11/SHP2中存在明显的突变(p.Glu76Gln、p.Glu76Ala和p.Gly503Val)。电子计算机分析表明，p.Glu76Gln和p.Glu76Ala而不是p.Gly503Val促进SHP2构象从折叠状态向开放活性状态的转变。SHP099能有效地抑制其中两个突变细胞系(SHP2 p.Glu76Gln或p.Glu76Ala)的生长，但不能抑制其他三个细胞系的生长。此外，SHP099抑制了含有SHP2 p.Glu76Ala突变的细胞系中ERK的激活。SHP2 p.Glu76Gln和p.Glu76Ala突变被认为是激活突变，推测SHP2 p.Glu76Ala的信号转导主要通过ERK途径进行。此外，对SHP099敏感的HS细胞，包括那些带有SHP2 p.Glu76Gln或p.Glu76Ala突变的HS细胞，可能依赖这些突变来生长。因此，用SHP099靶向携带SHP2p.Glu76Gln和P.Glu76Ala的细胞可能是治疗犬HS的一种途径。
Some canine cases of histiocytic sarcoma (HS) carry an activating mutation in the src homology two domain‐containing phosphatase 2 (SHP2) encoded byPTPN11. SHP099 is an allosteric inhibitor of SHP2 that stabilizes SHP2 in a folded, auto‐inhibited conformation. Here, we examined the expression and mutation status of SHP2 in five canine HS cell lines and evaluated the growth inhibitory properties of SHP099 against these cell lines. All five of the canine HS cell lines expressed SHP2, with three of the lines each harbouring a distinct mutation inPTPN11/SHP2 (p.Glu76Gln, p.Glu76Ala and p.Gly503Val). In silico analysis suggested that p.Glu76Gln and p.Glu76Ala, but not p.Gly503Val, promote shifting of the SHP2 conformation from folded to open‐active state. SHP099 potently suppressed the growth of two of the mutant cell lines (harbouring SHP2 p.Glu76Gln or p.Glu76Ala) but not that of the other three cell lines. In addition, SHP099 suppressed ERK activation in the cell line harbouring the SHP2 p.Glu76Ala mutation. The SHP2 p.Glu76Gln and p.Glu76Ala mutations are considered to be activating mutations, and the signal from SHP2 p.Glu76Ala is inferred to be transduced primarily via the ERK pathway. Moreover, SHP099‐sensitive HS cells, including those with SHP2 p.Glu76Gln or p.Glu76Ala mutations, may depend on these mutations for growth. Therefore, targeting cells harbouring SHP2 p.Glu76Gln and p.Glu76Ala with SHP099 may be an approach for the treatment of canine HS.