# Project 1:  Strategies to enhance MEK inhibitor efficacy in MUTNRAS melanoma

> **NIH NIH P01** · UNIVERSITY OF CALIFORNIA LOS ANGELES · 2020 · $517,920

## Abstract

PROJECT 1 ABSTRACT
Mutation-targeted small molecular inhibitors and immune checkpoint blockade or ICB (anti-PD-1 and -CTLA-4
antibodies) have extended the quality and quantity of life for patients with advanced BRAFMUT melanoma. Beyond
ICB, which is ineffective in up to 60% of patients, patients with advanced NRASMUT melanoma have no standard-
of-care options. Due to the rapid onset of resistance, MEK inhibitor (MEKi) monotherapy has limited clinical
activity against NRASMUT melanoma, with the potential exception of those melanoma previously exposed to ICB
(the NEMO trial). Here, we propose to design MEKi-based combinatorial-sequential regimens against advanced
NRASMUT melanoma. First, we will test the concept of priming MEKi responsiveness via anti-PD-1/L1
pretreatment (regardless of anti-PD-1/L1 sensitivity). We will test this concept as well as dissect the mechanisms
of action and innate/acquired resistance in human subjects (by conducting a phase II investigator-initiated trial)
and in syngeneic melanoma models. Second, we will test the concept of combining a next-generation RAF
inhibitor (RAFi) with a MEKi to overcome and to prevent MEKi resistance. These studies will be conducted in
human melanoma cell lines, patient-derived xenografts (PDXs), and syngeneic models. Third, we will test the
concept of overcoming MEKi resistance by pharmacologically exploiting a hallmark vulnerability of resistant
tumors: MEKi-addiction or tumor cell death induced by MEKi withdrawal. Specifically, to induce the regression
of a diverse array of NRASMUT MEKi-resistant PDX models, we will test one strategy involving sequencing from
a MEKi to a poly-ADP ribose polymerase inhibitor (PARPi) or another strategy involving rotations between MEKi
and PARPi. We will also test whether these sequencing/rotational strategies, by inducing various extents of
immunogenic cell death and/or innate immunity, would sensitize NRASMUT melanoma to combined anti-PD-1/L1
therapy. In these clinical and preclinical studies, we will derive multi-omic data and evaluate candidate pathways
to identify predictive biomarkers. In addition to bulk tumor-based, multi-omic analysis (exome, genome,
transcriptome, methylome, chromatin accessibility, proteome, TCR clonotypes) of longitudinal tumor samples,
we will also dissect the single-cell (scRNA-seq, CyTOF) evolution of NRASMUT melanoma to identify additional
combinatorial-sequential targets to overcome and then to prevent resistance. These studies require a close
collaboration with Projects 2 and 3 and Cores A-C at levels of shared technical expertise, reagents/models and
preliminary data, and this collaboration is grounded on a 10-year track record of joint publications that have
resulted in deep insights into clinically relevant melanoma biology, multiple clinical trials and even approved
therapies. The combination of oncology and dermatology expertise (Ribas and Lo) and laboratories with
complementary approaches (Ribas, Lo, Graeber) promises ...

## Key facts

- **NIH application ID:** 10025136
- **Project number:** 1P01CA244118-01A1
- **Recipient organization:** UNIVERSITY OF CALIFORNIA LOS ANGELES
- **Principal Investigator:** ROGER S LO
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $517,920
- **Award type:** 1
- **Project period:** 2020-09-11 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10025136

## Citation

> US National Institutes of Health, RePORTER application 10025136, Project 1:  Strategies to enhance MEK inhibitor efficacy in MUTNRAS melanoma (1P01CA244118-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10025136. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*