KSR as a therapeutic target for Ras-dependent cancers

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.

Analysis of NRAS RNA G-quadruplex binding proteins reveals DDX3X as a novel interactor of cellular G-quadruplex containing transcripts

“…We have therefore used an unbiased affinity proteomics approach to catalog cytoplasmic interactors of the human NRAS 5′-UTR rG4. This rG4 was selected due to the relevance of NRAS in tumorigenesis ( 22 ). Moreover, folding of the NRAS rG4 into a stable parallel intramolecular G4 is well-characterized biophysically and this rG4 has been shown to inhibit translation in vitro ( 20 ).…”

Discovery and validation of DNA methylation markers for overall survival prognosis in patients with thymic epithelial tumors

“…A recent study by Steven PD et al [19] reported that suppression of KSR1 gene expression could prolong survival in patients with colorectal cancer, and McCall JL et al [20] reported that the KSR1 gene affects Myc protein expression which affects the prognosis of patients with colon cancer. In addition, Neilsen BL [21] reported that KSR1 could be a therapeutic target for Ras-dependent cancers. With all the studies done on KSR1 , this is the first time KSR1 has been reported to affect the prognosis of patients with TETs.…”

<p>Ras-ERK1/2 Signaling Promotes The Development Of Osteosarcoma By Regulating H2BK12ac Through CBP</p>

“…The previous studies have demonstrated that the gene mutation of Ras is closely associated with the occurrence of malignancy 11,12. An interesting study demonstrated that Ras-ERK1/2 activation played a crucial role during tumor maintenance and which might be particularly important for the treatment of Ras-driven cancers 13. However, how the mutation of Ras affects the development of OS is still needed for further research.…”