# New Strategies for Treatment of NRAS Mutant Melanoma after Progression on Immune Checkpoint Inhibitors

> **NIH NIH R01** · VANDERBILT UNIVERSITY · 2021 · $379,970

## Abstract

Treatment of metastatic melanoma with immune checkpoint inhibitors (ICI) has extended the life of many melanoma
patients, but the vast majority of patient experience disease progression, prompting the need for alternate therapies.
For ~50% of patients with BRAFmut tumors, treatment with BRAF and MEK inhibitors provide a good second-line
treatment option. Unfortunately, there are few second-line options for the 25-30% of patients whose tumors harbor
NRAS mutations. Since nearly 40% of all melanoma patients exhibit loss, mutation, or epigenetic silencing of the
CDK4/6 regulator CDKN2A, we postulate that inhibition of CDK4/6 may induce response in NRASmut RBWT tumors
with loss of CDKN2A. Because loss of CDKN2A also disrupts ARF, a suppressor of MDM2-mediated degradation of
p53, it will be essential to also inhibit MDM2 to restore cell cycle control in p53WT melanoma. We have shown that
NRASmut melanoma tumors with acquired resistance to ICI respond to co-treatment with a CDK4/6 inhibitor plus an
MDM2, demonstrating both with reduced tumor growth and enhanced CD8+T cell recruitment into the tumor. These
tumors contain a significant number of CXCR1,2 expressing myeloid-derived suppressor cells (MDSCs) that create
an immune suppressive tumor microenvironment. Our preliminary data show that when CXCR2 is deleted in myeloid
cells, MDSC recruitment to tumor is reduced and tumor growth is inhibited. Moreover, systemic delivery of a CXCR1,2
inhibitor reduced the growth of NRASmut melanoma in mice (p<0.02), and inducible deletion of CXCR2 in melanocytes
blocks melanoma formation in the inducible BRAFV600E/PTEN-/- melanoma mouse model. These intriguing findings
support prior studies indicating a role for CXCR2 inhibitors for treatment of melanoma. However, the mechanisms
and generality of response to CXCR1,2 antagonism require further elucidation. Premise and Hypothesis: CXCR2
plays critical and pleotropic role in melanoma by promoting tumorigenesis and inducing an immunosuppressive tumor
environment. Moreover, combined CDK4/6 and MDM2 inhibition significantly inhibits the growth of mouse and human
NRASmut melanoma tumors. We hypothesize that co-inhibition of CXCR1,2, CDK4/6, and MDM2 in NRASmut
melanoma with acquired resistance to ICI will inhibit tumor cell proliferation, induce tumor cell death, stimulate anti-
tumor immunity, and potentially overcome the acquired resistance to ICI. We propose 3 specific aims. 1)To examine
the ability of CDK4/6i plus MDM2i, combined with a CXCR1,2 antagonist treatment, or CXCR1,2 agonist alone, to
enhance or restore ICI sensitivity for NRASmut melanoma tumors. 2) To determine the role of melanocyte-expressed
CXCR2 in melanoma initiation. CXCR2 will be deleted coincident with induction of melanoma formation in mice and
effects of this deletion on melanocyte apoptosis, senescence, differentiation and proliferation will be characterized.
3) To determine whether findings in mouse translate to human melanoma, changes in the tum...

## Key facts

- **NIH application ID:** 10144940
- **Project number:** 5R01CA116021-17
- **Recipient organization:** VANDERBILT UNIVERSITY
- **Principal Investigator:** Ann Richmond
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $379,970
- **Award type:** 5
- **Project period:** 2005-08-19 → 2025-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10144940

## Citation

> US National Institutes of Health, RePORTER application 10144940, New Strategies for Treatment of NRAS Mutant Melanoma after Progression on Immune Checkpoint Inhibitors (5R01CA116021-17). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10144940. Licensed CC0.

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