The ubiquitously expressed non-receptor protein tyrosine phosphatase SHP2, encoded by PTPN11, is involved in signal transduction downstream of multiple growth factor, cytokine and integrin receptors¹. Its requirement for complete RAS-MAPK activation and its role as a negative regulator of JAK-STAT signaling have established SHP2 as an essential player in oncogenic signaling pathways^1-7. Recently, a novel potent allosteric SHP2 inhibitor was presented as a viable therapeutic option for receptor tyrosine kinase-driven cancers, but was shown to be ineffective in KRAS-mutant tumor cell lines in vitro⁸. Here, we report a central and indispensable role for SHP2 in oncogenic KRAS-driven tumors. Genetic deletion of Ptpn11 profoundly inhibited tumor development in mutant KRAS-driven murine models of pancreatic ductal adenocarcinoma and non-small-cell lung cancer. We provide evidence for a critical dependence of mutant KRAS on SHP2 during carcinogenesis. Deletion or inhibition of SHP2 in established tumors delayed tumor progression but was not sufficient to achieve tumor regression. However, SHP2 was necessary for resistance mechanisms upon blockade of MEK. Synergy was observed when both SHP2 and MEK were targeted, resulting in sustained tumor growth control in murine and human patient-derived organoids and xenograft models of pancreatic ductal adenocarcinoma and non-small-cell lung cancer. Our data indicate the clinical utility of dual SHP2/MEK inhibition as a targeted therapy approach for KRAS-mutant cancers.

中文翻译：

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突变的KRAS驱动的癌症取决于PTPN11 / SHP2磷酸酶。

普遍表达的非受体蛋白酪氨酸磷酸酶SHP2，由PTPN11编码，参与多种生长因子，细胞因子和整联蛋白受体^1的下游信号转导。它的完全RAS-MAPK激活的要求及其作为JAK-STAT信号的负调节剂的作用已将SHP2确立为致癌信号通路^1-7的重要角色。最近，有人提出了一种新型的强力变构SHP2抑制剂，作为受体酪氨酸激酶驱动的癌症的可行治疗选择，但在体外KRAS突变肿瘤细胞株中却显示无效[ ^8]。。在这里，我们报告在致癌性KRAS驱动的肿瘤中SHP2的核心和必不可少的作用。Ptpn11的基因删除深刻地抑制了胰腺导管腺癌和非小细胞肺癌的突变KRAS驱动的小鼠模型中的肿瘤发展。我们提供了在癌变过程中突变KRAS对SHP2的关键依赖性的证据。在已建立的肿瘤中SHP2的删除或抑制延迟了肿瘤进展，但不足以实现肿瘤消退。但是，SHP2是阻断MEK时抵抗机制所必需的。当同时靶向SHP2和MEK时，观察到协同作用，从而在鼠和人患者衍生的类器官以及胰腺导管腺癌和非小细胞肺癌的异种移植模型中实现了对肿瘤生长的持续控制。