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.

KEYWORDS:

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

Article highlights

• Though ksr1^-/- mice are largely phenotypically normal, they have reduced ERK signaling and are resistant to Ras-driven tumorigenesis.

• Ksr2^-/- mice serve as an obesity model due to their increased adiposity, associated insulin resistance, and the detection of ksr2 mutations in some obese humans.

• KSR proteins are highly conserved from invertebrates to mammals and are structurally related to Raf proteins.

• The canonical function of KSR is as a scaffold for the Raf/MEK/ERK kinase cascade.

• KSR requires Ras activation and plasma membrane localization for activity where it forms a heterodimer with Raf to promote MEK and ERK phosphorylation and activation.

• The small molecule APS-2-79 binds to the ATP-binding domain of KSR proteins stabilizing them in an inactive state complexed with MEK, interfering with KSR:Raf heterodimerization, and inhibiting downstream Ras signaling.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Additional information

Funding

This manuscript was supported by funding from the National Institutes of Health, National Cancer Institute (F30 CA203397, P30 CA036727, RO1 CA157774, T32 CA009476).