Negative feedback and adaptive resistance to the targeted therapy of cancer

Abstract

Mutational activation of growth factor signaling pathways is commonly observed and often necessary for oncogenic transformation. Under physiologic conditions, these pathways are subject to tight regulation through negative feedback, which limits the extent and duration of signaling events after physiologic stimulation. Until recently, the role of these negative feedback pathways in oncogene-driven cancers has been poorly understood. In this review, I discuss the evidence for the existence and relevance of negative feedback pathways within oncogenic signaling networks, the selective advantages such feedback pathways may confer, and the effects such feedback might have on therapies aimed at inhibiting oncogenic signaling.

Significance: Negative feedback pathways are ubiquitous features of growth factor signaling networks. Because growth factor signaling networks play essential roles in the majority of cancers, their therapeutic targeting has become a major emphasis of clinical oncology. Drugs targeting these networks are predicted to inhibit the pathway but also to relieve the negative feedback. This loss of negative feedback can itself promote oncogenic signals and cancer cell survival. Drug-induced relief of feedback may be viewed as one of the major consequences of targeted therapy and a key contributor to therapeutic resistance.

Figures

Figure 1. Growth factor activation of signaling and negative feedback

Depicted in the first panel are major elements of the EGFR signaling transduction apparatus in a disassembled state in the absence of growth factor stimulation. In the second panel, addition of growth factor triggers receptor conformational change, receptor dimerization, receptor transphosphorylation, binding of adaptor proteins, activation of kinase cascades, and stimulation of cellular programs involved in transformation (cell cycle progression, evasion from apoptosis, motility and invasion, increases in cell size, stimulation of protein translation). In the third panel, negative feedback programs are depicted including ERK phosphorylation of SOS and RAF that downregulates their activity, induction of the CBL E3 ligase that lowers EGFR expression, FOXO mediated repression of expression of receptor tyrosine kinases such as HER3, and mTOR mediated destabilization of the IRS1 adaptor protein via S6K activation.

Figure 2. Negative feedback regulation of PI3K/AKT/mTOR signaling

Depicted in the top panel is negative feedback regulation of PI3K/AKT/mTOR signaling through two major pathways from mTOR and AKT. mTOR regulates adaptor proteins such as IRS1 while AKT regulates the expression of receptor tyrosine kinases (RTK) through the FOXO transcription factors. The consequence of drug inhibition of AKT is shown in the bottom left panel with inhibition of AKT causing loss of negative feedback on RTK expression and so inducing RTK expression. In addition, AKT in many cells activates mTOR and so drug inhibition of AKT leads to inhibition of mTOR leading to loss of negative feedback on IRS1. The sum consequence of AKT inhibition is to activate RTK function through adaptors and increases in RTK expression. Whereas, mTORC1 inhibition with rapamycin in the bottom right panel predominantly impacts RTK function through the effects on adaptor proteins without the effects on RTK expression.

Figure 3. Reciprocal feedback regulation of PI3K/AKT and AR signaling

On the left panel is a model depicting crosstalk between the PI3K/AKT pathway and the androgen receptor (AR) signaling pathway with each pathway negatively regulating the other. In the middle panel is the consequence of inhibiting AR signaling with downregulation of AR causing lower levels of FKBP5 and thus impairing the function of the AKT phosphatase PHLPP. The result is that AR inhibition causes an upregulation in AKT activity. In the right panel is the consequence of inhibiting PI3K/AKT signaling with downregulation of AKT causing an induction of RTKs such as HER3 and this causing an induction of AR signaling.