SHP2 Inhibition Prevents Adaptive Resistance to MEK Inhibitors in Multiple Cancer Models.
SHP2 Inhibition Prevents Adaptive Resistance to MEK Inhibitors in Multiple Cancer Models.
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DOI：
10.1158/2159-8290.cd-18-0444
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发表时间：
2018-10
期刊：
影响因子：
28.2
通讯作者：
Tang KH
中科院分区：
文献类型：
--
作者：
Fedele C;Ran H;Diskin B;Wei W;Jen J;Geer MJ;Araki K;Ozerdem U;Simeone DM;Miller G;Neel BG;Tang KH
对MEK抑制剂（MEK-Is）的适应性抗性通常通过诱导不同受体酪氨酸激酶（RTK）和/或其配体的基因而发生，即使在相同组织型的肿瘤中也是如此，使得组合策略具有挑战性。SHP 2（PTPN 11）是大多数RTK激活RAS/ERK通路所必需的，并可能提供一个共同的阻力节点。我们发现，将SHP 2抑制剂SHP 099与MEK-I组合在体外抑制多种癌细胞系的增殖。PTPN 11敲低/MEK-I处理具有类似的效果，而表达SHP 099结合缺陷型PTPN 11突变体赋予抗性，表明SHP 099是靶向的。SHP 099/曲美替尼在KRAS突变型胰腺癌、肺癌和卵巢癌的异种移植和/或基因工程模型以及野生型RAS表达三阴性乳腺癌中高度有效。SHP 099抑制具有残留GT3活性的KRAS突变体的活化，阻止SOS/RAS/MEK/ERK 1/2响应MEK-1的再活化，并阻断ERK 1/2依赖性转录程序。我们得出结论，SHP 099/MEK-I组合可能在多种恶性肿瘤中具有治疗效用。
Adaptive resistance to MEK inhibitors (MEK-Is) typically occurs via induction of genes for different receptor tyrosine kinases (RTKs) and/or their ligands, even in tumors of the same histotype, making combination strategies challenging. SHP2 (PTPN11) is required for RAS/ERK pathway activation by most RTKs, and might provide a common resistance node. We found that combining the SHP2 inhibitor SHP099 with a MEK-I inhibited the proliferation of multiple cancer cell lines in vitro. PTPN11 knockdown/MEK-I treatment had similar effects, while expressing SHP099 binding-defective PTPN11 mutants conferred resistance, demonstrating that SHP099 is on-target. SHP099/trametinib was highly efficacious in xenograft and/or genetically engineered models of KRAS-mutant pancreas, lung, and ovarian cancer and in wild type RAS-expressing triple negative breast cancer. SHP099 inhibited activation of KRAS mutants with residual GTPase activity, impeded SOS/RAS/MEK/ERK1/2 reactivation in response to MEK-Is and blocked ERK1/2-dependent transcriptional programs. We conclude that SHP099/MEK-I combinations could have therapeutic utility in multiple malignancies.