KSR as a therapeutic target for Ras-dependent cancers.
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.
a Eppley Institute, Fred & Pamela Buffett Cancer Center , University of Nebraska Medical Center , Omaha , NE , USA.
Beth K
BK
Neilsen
a Eppley Institute, Fred & Pamela Buffett Cancer Center , University of Nebraska Medical Center , Omaha , NE , USA.
Danielle E
DE
Frodyma
a Eppley Institute, Fred & Pamela Buffett Cancer Center , University of Nebraska Medical Center , Omaha , NE , USA.|b Department of Pathology and Microbiology , University of Nebraska Medical Center , Omaha , NE , USA.
Robert E
RE
Lewis
b Department of Pathology and Microbiology , University of Nebraska Medical Center , Omaha , NE , USA.
Kurt W
KW
Fisher
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D015195:Drug Design; D006801:Humans; D018345:Mice, Knockout; D058990:Molecular Targeted Therapy; D009369:Neoplasms / Q000473:pathology / Q000628:therapy*; D011494:Protein Kinases / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D015398:Signal Transduction; D018631:ras Proteins / Q000378:metabolism
D000970:Antineoplastic Agents; D011494:Protein Kinases; C097199:KSR-1 protein kinase; C557409:KSR2 protein, human; D017346:Protein Serine-Threonine Kinases; D018631:ras Proteins
APS-2-79; ERK; KSR1; KSR2; Kinase Suppressor of Ras; MEK; Raf; Ras signaling; Ras-dependent cancers; cancer therapeutics