Suppression of feedback loops mediated by PI3K/mTOR induces multiple overactivation of compensatory pathways: an unintended consequence leading to drug resistance.
Suppression of feedback loops mediated by PI3K/mTOR induces multiple overactivation of compensatory pathways: an unintended consequence leading to drug resistance.
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DOI：
10.1158/1535-7163.mct-14-0330
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发表时间：
2014-11
影响因子：
5.7
通讯作者：
Sinnet-Smith J
中科院分区：
文献类型：
--
作者：
Rozengurt E;Soares HP;Sinnet-Smith J
癌细胞产生耐药性被认为是药物失败和疾病进展的主要原因。PI 3 K/Akt/mTOR通路在许多癌细胞中被异常激活，因此它已成为治疗的靶点。然而，mTORC 1和S6 K也介导有效的负反馈回路，其减弱通过胰岛素/IGF受体和其他酪氨酸激酶受体的信号传导。这些反馈环的抑制导致上游途径的过度激活，包括PI 3 K、Akt和ERK，其潜在地对抗mTOR抑制剂的抗增殖作用并导致耐药性。这一概念的推论是负反馈环的释放和随后的促有丝分裂途径响应于信号抑制剂的补偿性过度激活可以规避通过仅靶向一种途径施加的促有丝分裂阻断。因此，阐明负反馈回路，调节信号网络的输出已成为一个领域的基本重要性，合理设计的有效的抗癌组合的抑制剂。在这里，我们回顾了在抑制上游信号反馈抑制的抑制剂作用下发生代偿性过度激活的通路，并强调了非预期通路激活在对临床相关的mTOR、Akt、PI 3 K或PI 3 K/mTOR抑制剂产生耐药性中的重要性。
The development of drug resistance by cancer cells is recognized as a major cause for drug failure and disease progression. PI3K/Akt/mTOR pathway is aberrantly stimulated in many cancer cells and thus it has emerged as a target for therapy. However, mTORC1 and S6K also mediate potent negative feedback loops that attenuate signaling via insulin/IGF receptor and other tyrosine kinase receptors. Suppression of these feedback loops causes over-activation of upstream pathways, including PI3K, Akt and ERK that potentially oppose the anti-proliferative effects of mTOR inhibitors and lead to drug resistance. A corollary of this concept is that release of negative feedback loops and consequent compensatory over-activation of pro-mitogenic pathways in response to signal inhibitors can circumvent the mitogenic block imposed by targeting only one pathway. Consequently, the elucidation of the negative feedback loops that regulate the outputs of signaling networks has emerged as an area of fundamental importance for the rational design of effective anticancer combinations of inhibitors. Here, we review pathways that undergo compensatory over-activation in response to inhibitors that suppress feedback inhibition of upstream signaling and underscore the importance of unintended pathway activation in the development of drug resistance to clinically relevant inhibitors of mTOR, Akt, PI3K or PI3K/mTOR.