# Dissecting and Targeting Deregulated Mitochondrial Apoptosis in Human Cancer

> **NIH NIH R35** · DANA-FARBER CANCER INST · 2024 · $999,639

## Abstract

PROJECT SUMMARY/ABSTRACT
BCL-2 proteins participate in a dynamic interaction network that determines whether a cell will live or die.
Deregulation of this essential signaling pathway underlies the pathogenesis of human cancer and resistance to
treatment. The goal of this R35 research program is to elucidate the fundamental protein interaction mechanisms
that drive the apoptotic program and harness these insights to develop next-generation cancer treatments. Over
the last five years of R35 support, we applied novel chemical tools and a host of analytical technologies to
achieve mechanistic discoveries that revealed new druggable binding sites and compounds to target them. We
found that covalent modification of distinct cysteines in pro-apoptotic BAX and anti-apoptotic MCL-1 and BFL-1
differentially regulate their apoptotic functions. Our pursuit of covalent ligands that mimic these post-translational
modifications are yielding prototype BAX activators and MCL-1 and BFL-1 inhibitors for cancer therapy.
Deciphering how BAX and BAK are directly activated, and the conformational mechanisms that underlie their
conversion from latent monomers into toxic mitochondrial oligomers, has also been a major focus of our work.
Indeed, the elusive structures of the BAX and BAK death channels represent the “holy grail” of apoptosis
research. We recently generated the first full-length homogeneous BAX oligomer (BAXO) amenable to structure-
function characterizations, providing a glimpse into the macromolecular organization of a functional BAXO
species. BAXO and its mutants are enabling us to pinpoint the structural determinants for each step of the BAX-
activation pathway and thus inform new control points for pharmacologic activation of apoptosis. In addition to
dissecting these high-priority, canonical BCL-2 protein interactions, we have developed proteomic tools to
identify non-canonical targets and recently found that MCL-1 directly interacts with the fatty acid oxidation
enzyme VLCAD, revealing a dual role for MCL-1 at the intersection of apoptosis and metabolic regulation. We
hypothesize that MCL-1-driven cancers rely on both apoptotic suppression and fatty acid metabolism to
maximize pathologic survival, potentially explaining why MCL-1 is the most widely expressed anti-apoptotic
protein across human cancers. Here, we build on our newest mechanistic insights to interrogate a spectrum of
BCL-2 family interactions that drive human cancer and mine each opportunity to pharmacologically subvert them.
Specifically, our next set of R35 goals are: (1) identify the structural and functional determinants that mediate
the “execution phase” of mitochondrial apoptosis; (2) solve the structure of a BAX oligomer; (3) characterize the
non-canonical role of MCL-1 at the intersection of apoptosis and cancer metabolism; and (4) advance the
development and in vivo testing of BCL-2 family molecular modulators as next-generation therapies for human
cancer. We tackle these goals u...

## Key facts

- **NIH application ID:** 10884507
- **Project number:** 5R35CA197583-11
- **Recipient organization:** DANA-FARBER CANCER INST
- **Principal Investigator:** Loren David Walensky
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $999,639
- **Award type:** 5
- **Project period:** 2015-08-24 → 2028-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10884507

## Citation

> US National Institutes of Health, RePORTER application 10884507, Dissecting and Targeting Deregulated Mitochondrial Apoptosis in Human Cancer (5R35CA197583-11). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10884507. Licensed CC0.

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