KSR as a therapeutic target for Ras-dependent cancers

Beth K. Neilsen, Danielle E. Frodyma, Robert E Lewis, Kurt W. Fisher

Research output: Contribution to journalReview article

6 Citations (Scopus)

Abstract

Introduction: Targeting downstream effectors required for oncogenic Ras signaling is a potential alternative or complement to the development of more direct approaches targeting Ras in the treatment of Ras-dependent cancers. Areas covered: Here we review literature pertaining to the molecular scaffold Kinase Suppressor of Ras (KSR) and its role in promoting signals critical to tumor maintenance. We summarize the phenotypes in knockout models, describe the role of KSR in cancer, and outline the structure and function of the KSR1 and KSR2 proteins. We then focus on the most recent literature that describes the crystal structure of the kinase domain of KSR2 in complex with MEK1, KSR-RAF dimerization particularly in response to RAF inhibition, and novel attempts to target KSR proteins directly. Expert opinion: KSR is a downstream effector of Ras-mediated tumorigenesis that is dispensable for normal growth and development, making it a desirable target for the development of novel therapeutics with a high therapeutic index. Recent advances have revealed that KSR can be functionally inhibited using a small molecule that stabilizes KSR in an inactive conformation. The efficacy and potential for this novel approach to be used clinically in the treatment of Ras-driven cancers is still being investigated.

Original languageEnglish (US)
Pages (from-to)499-509
Number of pages11
JournalExpert Opinion on Therapeutic Targets
Volume21
Issue number5
DOIs
StatePublished - May 4 2017

Fingerprint

Neoplasms
Therapeutics
ras Proteins
Dimerization
Expert Testimony
KSR-1 protein kinase
Growth and Development
Scaffolds
Conformations
Tumors
Carcinogenesis
Phosphotransferases
Crystal structure
Maintenance
Phenotype
Molecules
Proteins

Keywords

  • APS-2-79
  • cancer therapeutics
  • ERK
  • Kinase Suppressor of Ras
  • KSR1
  • KSR2
  • MEK
  • Raf
  • Ras signaling
  • Ras-dependent cancers

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology
  • Drug Discovery
  • Clinical Biochemistry

Cite this

KSR as a therapeutic target for Ras-dependent cancers. / Neilsen, Beth K.; Frodyma, Danielle E.; Lewis, Robert E; Fisher, Kurt W.

In: Expert Opinion on Therapeutic Targets, Vol. 21, No. 5, 04.05.2017, p. 499-509.

Research output: Contribution to journalReview article

Neilsen, Beth K. ; Frodyma, Danielle E. ; Lewis, Robert E ; Fisher, Kurt W. / KSR as a therapeutic target for Ras-dependent cancers. In: Expert Opinion on Therapeutic Targets. 2017 ; Vol. 21, No. 5. pp. 499-509.
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