# Preventing MAPK inhibitor resistance in melanoma by targeting genomic instability and immune resistance

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA LOS ANGELES · 2024 · $393,750

## Abstract

PROJECT SUMMARY
In the treatment of BRAFV600MUT melanoma, acquired resistance to MAPK inhibitor (MAPKi) limits its survival
benefits. Currently, MAPKi therapy is unavailable to patients with non-BRAFV600MUT melanoma. To improve
MAPKi therapy and to extend its application to more patients, we propose a project to develop two general
concepts to render MAPKi therapy more effective. Both concepts aim to prevent acquired MAPKi resistance by
targeting processes that are operative early on MAPKi therapy and that enable melanoma persisters to undergo
clonal evolution. In prior publications, we and others have shown that the selective pressure of MAPKi elicits (i)
a new round of genomic instability, leading to clonal diversification and selective expansion of clones that drive
acquired resistance and (ii) a new round of immune editing and hence immune resistance, leading to selective
expansion of clones that evade antitumor immunity (in particular cytotoxic T cells). We hypothesize that
therapeutic strategies that address these adaptive mechanisms in residual tumor cells on MAPKi therapy can
potentially prevent the seeds of acquired resistance. We expect that preventive approaches such as these,
combined with the more durable efficacy of antitumor immunity, should be more effective than conventional
approaches to target specific vulnerabilities of acquired resistance, due to extensive tumor heterogeneity and
clonal evolution resulting from disease progression.
In Aim 1, we build on our recent study showing that genomic instability such as chromothripsis gives rise to
amplicons that are selected by MAPKi to cause acquired resistance. These amplicons may be intrachromosomal
or extrachromosomal, the latter as circular ecDNAs. This finding led to further discovery that a combination to
block these mechanisms of genomic instability may prevent acquired resistance and the design of a trial testing
this combination as targeted therapy for NRASMUT melanoma. We hypothesize that the mechanisms by which
MAPKi elicits de novo genomic instability represent combinatorial targets to prevent acquired resistance. These
mechanisms involve the partial rupture of primary and micronuclear membranes, chromosome mis-segregation
and DNA-damaging proteins that aberrantly access normally protected chromosomal DNAs. In Aim 2, we build
on our recent published and unpublished studies showing that innate/adaptive immune resistance arises in
persisters early on MAPKi or immune checkpoint blockade (ICB) therapy, which results in PD-L1 accumulation
on the tumor surface. To diminish immune resistance, we identified a tool compound AK087 to degrade surface
PD-L1, thereby improving the efficacy of MAPKi (and ICB) therapy in immune-competent murine tumor models.
Here, we will dissect the mechanisms of action of AK087 to guide further the rational development of PD-L1
degraders as a general combinatorial strategy to improve the efficacy current melanoma therapies.

## Key facts

- **NIH application ID:** 10979966
- **Project number:** 2R01CA176111-11
- **Recipient organization:** UNIVERSITY OF CALIFORNIA LOS ANGELES
- **Principal Investigator:** ROGER S LO
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $393,750
- **Award type:** 2
- **Project period:** 2013-09-04 → 2029-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10979966

## Citation

> US National Institutes of Health, RePORTER application 10979966, Preventing MAPK inhibitor resistance in melanoma by targeting genomic instability and immune resistance (2R01CA176111-11). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10979966. Licensed CC0.

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