# Development of optimal strategies to inhibit ERK signaling in tumors with RAF and MEK mutations

> **NIH NIH R01** · SLOAN-KETTERING INST CAN RESEARCH · 2022 · $402,618

## Abstract

Development of optimal strategies to inhibit ERK signaling in tumors with RAF and MEK mutations
Abstract
Clinical tumor sequencing is increasingly being used in multiple cancer types to inform the care of individual
cancer patients. However, only a small number of mutant alleles are currently used by physicians to guide
treatment decisions, whereas most mutations, including those in well-studied cancer genes such as BRAF,
remain of unknown biologic and clinical significance. The long-term objective of this proposal is to expand the
clinical utility of sequencing by understanding the mechanisms of activation of the broader array of mutant
alleles in the RAF and MEK kinases and their sensitivity to selective pharmacologic inhibitors of RAF, MEK,
and ERK. By directly comparing the sensitivity of cellular models to patient responses, within the context of a
co-clinical trial paradigm, we seek to expand the population of patients who benefit from treatment with ERK
pathway inhibitors. Three specific aims are proposed. In Aim 1, we will biologically characterize BRAF, CRAF
(RAF1), ARAF, MEK1, and MEK2 variants of unknown biologic and clinical significance identified in patients
treated with RAF, MEK, and ERK inhibitors. Prioritization for detailed functional studies will be given to RAF or
MEK mutant alleles of unknown clinical significance identified in patients treated with novel ERK pathway
inhibitors within the context of clinical trials. Studies will be performed using engineered isogenic cell lines and
patient-derived xenograft (PDX) and cell line models. In Aim 2, we will identify mechanisms of acquired
resistance to RAF dimer inhibitors, a novel class of RAF inhibitors that has shown promising activity in
preclinical models driven by non-V600 BRAF mutations, including BRAF fusions, which are intrinsically
resistant to current FDA-approved RAF inhibitors such as vemurafenib. Specifically, we will utilize laboratory
models selected for acquired resistance to RAF dimer inhibitors in parallel with pretreatment and disease-
progression biopsies of patients treated with these agents to identify and functionally validate mechanisms of
acquired resistance to RAF dimer inhibitors. Finally, in Aim 3, we will identify and validate mechanisms of
resistance to MEK and ERK inhibitors in patients with activating mutations of MEK1 and MEK2. In both Aims 2
and 3, we will utilize a custom, next-generation sequencing platform designed to detect putative resistance
mutations using cell-free DNA to define the timing at which such alterations arise during drug treatment. By
distinguishing those RAF and MEK mutations that are biologically functional from those that are passenger
mutations, and by defining the sensitivity of the former to FDA-approved and investigational targeted inhibitors
of this pathway, the studies proposed here will expand the treatment options for this molecularly defined subset
of cancer patients. The models of non-V600E BRAF-, A/CRAF-, or MEK1...

## Key facts

- **NIH application ID:** 10438820
- **Project number:** 5R01CA229624-05
- **Recipient organization:** SLOAN-KETTERING INST CAN RESEARCH
- **Principal Investigator:** David B. Solit
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $402,618
- **Award type:** 5
- **Project period:** 2018-06-14 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10438820

## Citation

> US National Institutes of Health, RePORTER application 10438820, Development of optimal strategies to inhibit ERK signaling in tumors with RAF and MEK mutations (5R01CA229624-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10438820. Licensed CC0.

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