# Targeting Oncogenic Ras-MAPK Signaling Complexes via the Scaffold KSR

> **NIH NIH R01** · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · 2021 · $417,453

## Abstract

Kinase suppressor of RAS (KSR) is a mitogen-activated protein kinase (MAPK) scaffold that is subject to
allosteric regulation through dimerization with RAF. Studies in model organisms suggest that direct targeting of
KSR could have important therapeutic implications for cancer therapy; however, testing this hypothesis through
pharmacological approaches has been difficult owing to a lack of small molecule antagonists of KSR function.
We have recently identified a promising set of lead compounds that bind directly to KSR to antagonize
oncogenic RAS-MAPK signaling (Dhawan et al., Nature, 2016). This unique class of small molecules, which
operate through stabilization of the KSR inactive state (KSRi), antagonize RAS-MAPK signaling by impeding
RAF-KSR heterodimerization and conformational changes required for activation of the RAS-effector kinase
MEK. Furthermore, we have found that KSRi has the potential to increase the efficacy of currently available
MAPK inhibitors (including MEK inhibitors) by increasing therapeutic index, thereby expanding the potential
utility of currently available MAPK inhibitors to treat patients with RAS-mutant cancers. Our preliminary studies
have been based on in vitro studies, including reconstitution assays, cell line studies, and crystallographic
analysis. In this proposal, we build upon our early leads so to create novel chemical probes that would be
suitable for in vivo experiments. Compounds that emerge from this work will be valuable tools for the
investigation of RAS-MAPK mechanisms, targets, and therapeutics.
Furthermore, we will investigate direct targeting of KSR as a mechanism to inhibit deregulated RAS-MAPK
pathway signaling within patient-derived and drug resistant cancer models. The RAS-MAPK pathway is
activated in approximately 25% of human cancers, most often through point mutations in K-RAS. Deregulation
of the RAS-MAPK pathway in patients is believed to be a major determinant of cancer initiation, progression,
metastases, and often resistance to targeted therapies. Certain subtypes of cancer show a high percentage of
RAS mutations; it is estimated that 95% of pancreatic cancers, 35% of colorectal, and 25% of lung cancers are
dependent on mutant RAS-MAPK signaling. Currently, there are limited therapeutic options for these large
patient populations. Small molecule targeting of KSR offers a novel approach to modulate RAS signaling
pathways in disease, which if successful, could impact a high number of cancer patients.

## Key facts

- **NIH application ID:** 10104458
- **Project number:** 5R01CA227636-04
- **Recipient organization:** ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
- **Principal Investigator:** Arvin Dar
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $417,453
- **Award type:** 5
- **Project period:** 2018-03-15 → 2023-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10104458

## Citation

> US National Institutes of Health, RePORTER application 10104458, Targeting Oncogenic Ras-MAPK Signaling Complexes via the Scaffold KSR (5R01CA227636-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10104458. Licensed CC0.

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