Suppression of feedback loops mediated by PI3K/mTOR induces multiple over-activation of compensatory pathways: an unintended consequence leading to drug resistance

摘要

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.