SHP2 Drives Adaptive Resistance to ERK Signaling Inhibition in Molecularly Defined Subsets of ERK-Dependent Tumors
SHP2 Drives Adaptive Resistance to ERK Signaling Inhibition in Molecularly Defined Subsets of ERK-Dependent Tumors
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DOI：
10.1016/j.celrep.2018.12.013
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发表时间：
2019-01-02
期刊：
影响因子：
8.8
通讯作者：
Poulikakos, Poulikos I.
中科院分区：
文献类型：
--
作者：
Ahmed, Tamer A.;Adamopoulos, Christos;Poulikakos, Poulikos I.
在ERK依赖的肿瘤中，ERK信号的药物靶向常常受到适应性抵抗的限制，通常由RTK信号的反馈激活和ERK活性的反弹介导。在这里，我们展示了ERK信号和SHP2磷酸酶的联合药理学靶向在确定的ERK依赖的肿瘤亚群中防止适应性耐药。在每个对联合治疗敏感的肿瘤中，观察到p(Y542)SHP2对ERK信号通路的抑制有反应。该策略在TNBC模型和G12具有RAS突变的肿瘤中广泛有效，而具有RAS(G13D)或RAS(Q61X)突变的肿瘤则具有耐药性。此外，我们确定了BRAF(V600E)肿瘤的一个子集，这些肿瘤对联合治疗具有耐药性，其中FGFR被发现独立于SHP2驱动反馈诱导的RAS激活。因此，我们确定了ERK依赖肿瘤中联合ERK信号和SHP2抑制反应的分子决定因素。
Pharmacologic targeting of components of ERK signaling in ERK-dependent tumors is often limited by adaptive resistance, frequently mediated by feedback-activation of RTK signaling and rebound of ERK activity. Here, we show that combinatorial pharmacologic targeting of ERK signaling and the SHP2 phosphatase prevents adaptive resistance in defined subsets of ERK-dependent tumors. In each tumor that was sensitive to combined treatment, p(Y542) SHP2 induction was observed in response to ERK signaling inhibition. The strategy was broadly effective in TNBC models and tumors with RAS mutations at G12, whereas tumors with RAS(G13D) or RAS(Q61X) mutations were resistant. In addition, we identified a subset of BRAF(V600E) tumors that were resistant to the combined treatment, in which FGFR was found to drive feedback-induced RAS activation, independently of SHP2. Thus, we identify molecular determinants of response to combined ERK signaling and SHP2 inhibition in ERK-dependent tumors.