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

ABSTRACT: The development of drug resistance by cancer cells is recognized as a major cause for drug failure and disease progression. The 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/insulin growth factor receptor and other tyrosine kinase receptors. Suppression of these feedback loops causes overactivation of upstream pathways, including PI3K, AKT, and ERK that potentially oppose the antiproliferative effects of mTOR inhibitors and lead to drug resistance. A corollary of this concept is that release of negative feedback loops and consequent compensatory overactivation of promitogenic pathways in response to signal inhibitors

SUBMITTER: Rozengurt E 

PROVIDER: S-EPMC4222988 | biostudies-literature | 2014 Nov

REPOSITORIES: biostudies-literature