# FOSL1-super-enhancers define cisplatin-enriched cancer stem cells in HNSCC

> **NIH NIH R01** · VIRGINIA COMMONWEALTH UNIVERSITY · 2024 · $517,993

## Abstract

Project Summary/Abstract
The chemotherapeutic drug cisplatin is a first-line drug for the treatment of many solid tumors, especially head
and neck squamous cell carcinoma (HNSCC). However, resistance to cisplatin has become a major obstacle to
effective cancer therapy. Cisplatin is well-known to enrich the cancer stem cell (CSC) population, which can
contribute to chemoresistance. Accordingly, targeting CSCs may represent an effective strategy to overcome
cisplatin resistance. Previously, we demonstrated that FOSL1 promotes tumorigenesis and metastasis of
HNSCC through establishing Super-Enhancers (SEs) at key cancer stemness and pro-metastatic genes, and
furthermore, disruption of FOSL1-SEs suppresses HNSCC growth and metastasis. Additionally, we have
discovered that increased FOSL1 activity facilitates cisplatin resistance of CSCs in a spontaneous mouse model
of HNSCC. Taken together, we believe that the FOSL1-SE-dependent transcription program may represent a
novel target for overcoming cisplatin resistance in HNSCC. To validate this, the key scientific questions of
whether FOSL1-SEs are present in cisplatin-enriched CSCs and how to determine their functional properties
must be addressed, as these FOSL1-SEs were originally characterized using whole HNSCC cell populations
only. Currently, no effective FOSL1 inhibitors are available, which hinders our further mechanistic and functional
studies. Proteolysis Targeting Chimeras (PROTAC) is a novel approach to selectively and potently degrade a
protein of interest (POI) both in vitro and in vivo. In this approach, a hetero-functional molecule is designed to
contain an inhibitor that binds to a POI, another small-molecule ligand which binds to an E3 ubiquitin ligase
complex, and a linker to tether these two ligands together. In our preliminary studies, we have designed and
synthesized a group of novel PROTAC-based FOSL1 degraders, from a parental FOSL1 inhibitor. The top
compound can potently degrade FOSL1 to eliminate CSCs in vivo, displaying advantages over the parent
inhibitor. Therefore, we hypothesize that FOSL1-SEs determine the functional properties of cisplatin-enriched
CSCs in HNSCC, and serve as a promising target for overcoming cisplatin resistance in HNSCC, which can be
validated by utilizing the effective PROTAC-based FOSL1 degraders. We propose the following specific aims to
test our hypotheses. Aim 1: Investigate the mechanism of action of FOSL1-SEs in determining the functional
properties of cisplatin-enriched CSCs in HNSCC and apply PROTACs to validate such a mechanism of action.
Aim 2: Initiate SAR studies and a functional screening to identify the top PROTACs to target FOSL1-SEs
effectively in HNSCC from a library of 100 candidates. The goal is to identify optimal compounds for mechanistic
(Aim 1) and functional validations (Aim 3). Aim 3: Validate whether targeting FOSL1-SEs with PROTAC
molecules (top 2 compounds from Aim 2) can efficiently eliminate CSCs and overcome cisplatin re...

## Key facts

- **NIH application ID:** 11049626
- **Project number:** 1R01DE033712-01A1
- **Recipient organization:** VIRGINIA COMMONWEALTH UNIVERSITY
- **Principal Investigator:** Jiong Li
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $517,993
- **Award type:** 1
- **Project period:** 2024-09-02 → 2029-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11049626

## Citation

> US National Institutes of Health, RePORTER application 11049626, FOSL1-super-enhancers define cisplatin-enriched cancer stem cells in HNSCC (1R01DE033712-01A1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/11049626. Licensed CC0.

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