Negative feedback and adaptive resistance to the targeted therapy of cancer. Review uri icon

Overview

abstract

  • UNLABELLED: 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.

publication date

  • March 22, 2012

Research

keywords

  • Drug Resistance, Neoplasm
  • Molecular Targeted Therapy
  • Neoplasms
  • Signal Transduction

Identity

PubMed Central ID

  • PMC3351275

Scopus Document Identifier

  • 84864012288

Digital Object Identifier (DOI)

  • 10.1158/2159-8290.CD-12-0018

PubMed ID

  • 22576208

Additional Document Info

volume

  • 2

issue

  • 4