Phosphorylation of SHP2 at Tyr62 Enables Acquired Resistance to SHP2 Allosteric Inhibitors in FLT3-ITD-Driven AML.
Phosphorylation of SHP2 at Tyr62 Enables Acquired Resistance to SHP2 Allosteric Inhibitors in FLT3-ITD-Driven AML.
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在FLT 3-ITD驱动的AML中，SHP 2在Tyr 62处的磷酸化能够获得对SHP 2变构抑制剂的抗性。
DOI：
10.1158/0008-5472.can-21-0548
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发表时间：
2022-06-06
期刊：
影响因子：
11.2
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中科院分区：
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这些发现表明，联合抑制SHP 2和FLT 3可有效治疗FLT 3-ITD阳性AML，这突出表明需要开发更有效的SHP 2抑制剂和联合疗法用于临床应用。蛋白酪氨酸磷酸酶SHP 2对于表达突变的受体酪氨酸激酶的急性髓性白血病（AML）细胞的致癌转化至关重要。SHP 2是完全RAS-ERK激活所必需的，以促进细胞增殖和存活程序。变构SHP 2抑制剂通过使SHP 2稳定在其自身抑制构象中起作用，并且目前正在单独和以各种药物组合用于RAS/ERK通路过度活化的肿瘤的临床试验中进行测试。在这项研究中，我们从两个FLT 3-ITD（内部串联重复）阳性AML细胞系中建立了对变构SHP 2抑制剂SHP 099具有获得性抗性的细胞。这些耐药模型的无标记和同量异位素标记定量质谱磷酸化蛋白质组学证明，AML细胞可以在SHP 099存在下恢复磷酸化ERK（pERK），从而产生适应性耐药。从机制上讲，SHP 2抑制诱导酪氨酸磷酸化和反馈驱动的FLT 3受体激活，进而磷酸化酪氨酸62上的SHP 2。这种磷酸化使SHP 2稳定在其开放构象，阻止SHP 099结合并赋予抗性。SHP 2和MEK或FLT 3的组合抑制防止pERK反弹和抗性细胞生长。在FLT 3突变的B细胞急性淋巴细胞白血病细胞系和inv（16）/KitD 816 Y AML小鼠模型中观察到相同的机制，但Shp 2的变构抑制不会损害正常骨髓祖细胞的克隆形成能力。总之，这些结果支持未来将SHP 2抑制剂组合用于临床应用。这些发现表明，联合抑制SHP 2和FLT 3可有效治疗FLT 3-ITD阳性AML，这突出表明需要开发更有效的SHP 2抑制剂和联合疗法用于临床应用。
These findings suggest that combined inhibition of SHP2 and FLT3 effectively treat FLT3-ITD–positive AML, highlighting the need for development of more potent SHP2 inhibitors and combination therapies for clinical applications. The protein tyrosine phosphatase SHP2 is crucial for oncogenic transformation of acute myeloid leukemia (AML) cells expressing mutated receptor tyrosine kinases. SHP2 is required for full RAS-ERK activation to promote cell proliferation and survival programs. Allosteric SHP2 inhibitors act by stabilizing SHP2 in its autoinhibited conformation and are currently being tested in clinical trials for tumors with overactivation of the RAS/ERK pathway, alone and in various drug combinations. In this study, we established cells with acquired resistance to the allosteric SHP2 inhibitor SHP099 from two FLT3-ITD (internal tandem duplication)-positive AML cell lines. Label-free and isobaric labeling quantitative mass spectrometry–based phosphoproteomics of these resistant models demonstrated that AML cells can restore phosphorylated ERK (pERK) in the presence of SHP099, thus developing adaptive resistance. Mechanistically, SHP2 inhibition induced tyrosine phosphorylation and feedback-driven activation of the FLT3 receptor, which in turn phosphorylated SHP2 on tyrosine 62. This phosphorylation stabilized SHP2 in its open conformation, preventing SHP099 binding and conferring resistance. Combinatorial inhibition of SHP2 and MEK or FLT3 prevented pERK rebound and resistant cell growth. The same mechanism was observed in a FLT3-mutated B-cell acute lymphoblastic leukemia cell line and in the inv(16)/KitD816Y AML mouse model, but allosteric inhibition of Shp2 did not impair the clonogenic ability of normal bone marrow progenitors. Together, these results support the future use of SHP2 inhibitor combinations for clinical applications. These findings suggest that combined inhibition of SHP2 and FLT3 effectively treat FLT3-ITD–positive AML, highlighting the need for development of more potent SHP2 inhibitors and combination therapies for clinical applications.