# Melanoma Resistance to Apoptosis: Mechanisms and Therapeutic Potential

> **NIH VA I01** · VA EASTERN COLORADO HEALTH CARE SYSTEM · 2023 · —

## Abstract

The incidence of melanoma is increasing rapidly in the VA population in the United States, and sun
exposure during US military service has been linked to increased melanoma incidence. The standard of care
for advanced melanomas includes molecular-targeted therapies of BRAF and MEK inhibitors, as well as
immunotherapies with checkpoint inhibitors such as anti-PD1. However, between 25% to 70% of advanced
melanoma patients either do not respond or relapse from the current treatments. Therefore, discovering
effective new therapies for malignant melanoma is still a pressing issue in the VA patient care mission.
 BH3 mimetics are a potent new class of cancer treatments that inhibit the BCL-2 dependent anti-apoptotic
defenses inherent in cancer cells. Standard care plus an inhibitor against BCL-2 (Venetoclax) gave a
response rates as high as ~80% in hematological malignancies. However, treatment with a single BH3 mimetic
is insufficient to kill solid tumors, likely due to the presence of uninhibited BCL-2 family members. MCL-1
inhibitors, currently in clinical trials, can potentially boost treatment effectiveness when paired with clinically
established BH3 mimetics. Further, most studies with BH3 mimetics focus on their ability to kill tumor cells
directly, while their potential to enhance immunotherapies remains to be explored. The objective of this
project is to test the combination treatment of MCL-1 inhibitors with other BH3 mimetics or with
immunotherapy (anti-PD-1) in the treatment of melanoma, especially for melanoma tumor cells
unresponsive to current treatments.
 Our preliminary data have indicated that MCL-1 inhibitors, when combined with ABT-263, can
synergistically kill both the bulk of melanoma tumor cells and the melanoma initiating cells (MICs). The
melanomas included those relapsed from current therapies. Further, in an immune competent model for
melanoma (B16 in C57BL6 mice), a MCL-1 inhibitor increased the efficacy of anti-PD1 therapy (Preliminary
Studies). We hypothesize: 1) MCL-1 inhibitors, as part of combination therapies, can overcome the resistance
of melanoma patients to current treatments. 2) This elimination of tumor cells can be achieved either through
direct killing or through modulating the antitumor immune response of tumor microenvironment. We also have
access to a large collection of melanoma short-term cultures and patient-derived xenograft (PDX) models from
the University of Colorado Melanoma Tissue Bank. Most of these materials were derived from melanomas of
patients who had relapsed from the current treatments, with whole exosome and RNA-seq data available; they
will provide the unique opportunity to test our hypotheses. Aim 1 will determine the mechanism(s) at play in the
combination of MCL-1 inhibitors and ABT-263. We will further test the hypothesis that the combination of
multiple BH3 mimetics, targeting MCL-1 plus other pro-survival BCL-2 family members, will overcome the
resistance of melanoma cells to current ...

## Key facts

- **NIH application ID:** 10695992
- **Project number:** 5I01BX000141-12
- **Recipient organization:** VA EASTERN COLORADO HEALTH CARE SYSTEM
- **Principal Investigator:** DAVID A. NORRIS
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2023
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2009-10-01 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10695992

## Citation

> US National Institutes of Health, RePORTER application 10695992, Melanoma Resistance to Apoptosis: Mechanisms and Therapeutic Potential (5I01BX000141-12). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10695992. Licensed CC0.

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