Efficacy of Allosteric SHP2 Inhibitor in RAS Mutant-Driven Myeloid Neoplasms

别构SHP2抑制剂对RAS突变驱动的髓系肿瘤的疗效 项目摘要/摘要 髓系肿瘤是一组干细胞来源的血液系统恶性肿瘤，其特征是髓系细胞的异常产生。慢性粒单核细胞白血病(CMML)和幼年粒单核细胞白血病(JMML)均为侵袭性骨髓增生性肿瘤(MPN)，临床转归较差。目前的化疗方法不足以治疗CMML和JMML。在~40%的CMML和~30%的JMML病例中发现RAS的体细胞突变。直接抑制致癌RAS尚未成功。因此，靶向RAS调控因子或效应分子可能是治疗RAS突变所致MPN的有效策略。在RAS突变型表达细胞中，MEK/ERK通路的异常激活是常见的现象。虽然MEK抑制剂治疗可以减少细胞增殖，但它只能部分改善KRAS突变小鼠的MPN表型。此外，MEK抑制剂治疗未能减少骨髓中RAS突变的造血祖细胞，尽管正在进行治疗，但一些小鼠出现了T系急性淋巴细胞白血病(T-ALL)。因此，有必要寻找新的治疗靶点(S)，并开发新的靶向治疗肿瘤RAS驱动的MPN(CMML和JMML)。Shp2调控Ras/RAF/MEK/ERK通路。SHP2基因缺失或药物抑制可阻断RAS/RAF/MEK/ERK通路的激活。因此，我们推测SHP2的抑制在治疗RAS突变驱动的MPN(CMML和JMML)中可能是有用的。为了检验我们的假设，我们提出了两个具体目标。具体目的1确定变构SHP2抑制剂SHP099对RAS突变造血细胞/祖细胞和KrasG12D敲打小鼠模型MPN的疗效。特异性靶点2将确定SHP099处理抑制RAS突变体驱动的MPN的机制。我们建议的研究将确定靶向SHP2是否对致癌的RAS驱动的MPN有效。此外，这些研究的结果将为变构SHP2抑制剂治疗CMML和JMML的临床试验奠定基础。

Title: Efficacy of Allosteric SHP2 Inhibitor in RAS Mutant-Driven Myeloid Neoplasms Project Summary/Abstract Myeloid neoplasms are a group of stem cell-derived hematologic malignancies characterized by abnormal production of myeloid lineage cells. Chronic myelomonocytic leukemia (CMML) and juvenile myelomonocytic leukemia (JMML) are aggressive myeloproliferative neoplasms (MPN) that have poor clinical outcome. Current chemotherapies are not adequate to treat CMML and JMML. Somatic mutations in RAS are found in ~40% of CMML and ~30% of JMML cases. Direct inhibition of oncogenic RAS has not been successful. Therefore, targeting of RAS regulator or effector could be a useful strategy in treating MPN driven by RAS mutants. Aberrant activation of the MEK/ERK pathway is commonly observed in RAS mutant expressing cells. Although MEK inhibitor treatment can reduce cell proliferation, it only partially improves MPN phenotype in KRAS mutant mice. Furthermore, MEK inhibitor treatment failed to reduce the RAS mutant hematopoietic progenitors in the bone marrow, and T-lineage acute lymphoblastic leukemia (T-ALL) emerged in some mice despite ongoing treatment. So, there is a need to identify new therapeutic target(s) and develop novel targeted therapies for oncogenic RAS-driven MPN (CMML and JMML). SHP2 regulates the RAS/RAF/MEK/ERK pathway. Genetic deletion or pharmacologic inhibition of SHP2 abrogates the activation of the RAS/RAF/MEK/ERK pathway. So, we hypothesize that inhibition of SHP2 might be useful in treating RAS mutant-driven MPN (CMML and JMML). To test our hypothesis, we propose two specific aims. Specific Aim 1 will determine the efficacy of allosteric SHP2 inhibitor SHP099 against RAS mutant hematopoietic cells/progenitors and KRasG12D knockin mouse model of MPN. Specific Aim 2 will determine the mechanism of inhibition of RAS mutant-driven MPN by SHP099 treatment. Our proposed studies will determine if targeting of SHP2 is effective against oncogenic RAS-driven MPN. Moreover, results from these studies will lay the groundwork for clinical trials of allosteric SHP2 inhibitor for treatment of CMML and JMML.