# Mechanisms of nuclear Mcl-1 mediated chemoresistance

> **NIH NIH R01** · CLEVELAND CLINIC LERNER COM-CWRU · 2021 · $368,288

## Abstract

Abstract
The overexpression of anti-apoptotic Bcl-2 proteins is a primary mechanism by which tumors protect themselves
from chemotherapeutic interventions. Most effort in the field has focused on a specific molecular domain that is
common to the anti-apoptotic Bcl-2 family proteins, which binds and prevents pro- apoptotic family members
from initiating programmed cell death by the mitochondrial pathway. Our preliminary data, however, indicate that
Mcl-1 protects tumors from therapeutic interventions by a second mechanism, independent of its anti-apoptotic
activities. Specifically, our data indicate that Mcl-1 contains a unique loop domain that binds proteins that regulate
gene expression when the molecule is translocated from the mitochondrion to the nucleus in response to
chemotherapy. Specifically, the data demonstrate that once localized to the nucleus, Mcl-1 interacts with
machinery known to regulate RNA stability, and directly suppresses the expression of transcripts normally
upregulated in chemosensitive cells, including genes involved in the production of reactive oxygens species such
as NOX4. We use colorectal cancer as our model, solid tumor because: 1) it continues to be one of the deadliest
human cancers; 2) mounting data indicates that Mcl-1 plays a major role in regulating chemoresistance in colon
cancer; and 3) we have access to a very large colorectal cancer tumor bank, from which we have generated
numerous patient-derived models. It is our hypothesis that Mcl-1’s role in chemoresistance depends on its ability
to leave the mitochondria and translocate to the nucleus, and to post-transcriptionally coordinate a stress
response to cope with chemotherapy-induced oxidative stress. We thus hypothesize that to optimize targeting
of Mcl-1, a combinatorial approach is necessary, whereby inhibitors of both its anti-apoptotic mechanism and
the loop domains mediating its nuclear activities will provide the comprehensive strategy needed to overcome
the tumor’s chemoresistance. We propose the following three related but independent aims to test our hypothesis:
1) Determine the mechanism by which chemotherapy induces Mcl-1 nuclear translocation. 2) Investigate the
mechanism by which nuclear Mcl-1 mediates chemoresistance. 3) Develop strategies that target Mcl-1’s multiple
mechanisms of chemoresistance. Successful completion of these aims will yield new targets for rendering tumors
chemosensitive and will provide the understanding needed for anti-Mcl-1 drug design for colorectal- and
ultimately other forms of cancer. As there is significant pharmaceutical interest in designing inhibitors of Mcl-1
for solid tumor therapy, our proposal is extremely timely for attaining the molecular understanding of the molecule
requisite for successfully accomplishing that goal.

## Key facts

- **NIH application ID:** 10121789
- **Project number:** 1R01CA244958-01A1
- **Recipient organization:** CLEVELAND CLINIC LERNER COM-CWRU
- **Principal Investigator:** BRIAN R GASTMAN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $368,288
- **Award type:** 1
- **Project period:** 2020-12-04 → 2025-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10121789

## Citation

> US National Institutes of Health, RePORTER application 10121789, Mechanisms of nuclear Mcl-1 mediated chemoresistance (1R01CA244958-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10121789. Licensed CC0.

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