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Negative feedback and adaptive resistance to the targeted therapy of cancer

Sarat Chandarlapaty1

  • 1Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA. chandars@mskcc.org

Cancer Discovery
|May 12, 2012
PubMed
Abstract

Insights

Negative feedback pathways regulate growth factor signaling. In cancer, these pathways can be reactivated by therapies, promoting cancer cell survival and therapeutic resistance.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Signaling Networks

Background:

  • Growth factor signaling pathways are crucial for cell growth and are frequently activated in cancer.
  • Physiologic conditions involve tight regulation of these pathways by negative feedback mechanisms.
  • The role of negative feedback in oncogene-driven cancers was previously under-investigated.

Purpose of the Study:

  • To review the evidence for negative feedback pathways in oncogenic signaling networks.
  • To discuss the selective advantages conferred by these feedback pathways.
  • To examine the impact of negative feedback on therapies targeting oncogenic signaling.

Main Methods:

  • Review of existing literature on negative feedback in growth factor signaling.
  • Analysis of the role of negative feedback in oncogene-driven cancers.
  • Discussion of therapeutic implications of negative feedback modulation.

Main Results:

  • Negative feedback pathways are integral components of growth factor signaling networks.
  • These pathways can confer selective advantages in the context of oncogenesis.
  • Targeting oncogenic signaling pathways can inadvertently relieve negative feedback.

Conclusions:

  • Relief of negative feedback by targeted therapies can promote oncogenic signals and cancer cell survival.
  • Drug-induced relief of feedback is a significant consequence of targeted therapy.
  • This mechanism is a key contributor to therapeutic resistance in cancer treatment.

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