# Molecular Mechanisms Underlying the Prevention of BCC Resistance

> **NIH NIH R01** · COLUMBIA UNIVERSITY HEALTH SCIENCES · 2024 · $364,500

## Abstract

SUMMARY
BCCs are the most common type of human malignancy in the US, affecting more than 3 million Americans
annually. Defective regulation of Hedgehog (Hh) signaling, typically through loss of function of the tumor
suppressor Patched (PTCH) leading to oncogenic activation of SMO, are thought to be the primary drivers of
BCC growth. Ligand binding to PTCH relieves SMO repression, triggering its migration to the primary cilium with
activation of GLI transcription factors that drive cell proliferation/tumor growth. Aberrant HH signaling underlies
the Gorlin-Goltz syndrome, also known as basal cell nevus syndrome(BCNS), a dominantly inherited disorder in
which affected individuals are born with one functional PTCH allele and during life acquire mutations in the
second allele that accelerate HH signaling and drive the growth of BCCs in these patients whose inordinate
tumor burden necessitates multiple costly mutilating surgical procedures over their lifetime. Furthermore, Hh
inhibitors (HHi) are associated with intolerable side-effects in treated individuals such that half the patients
discontinue treatment despite substantial anti-tumor efficacy. Our group and others around the world have
fostered bench-to-bedside clinical trials with drugs that target HH signaling and in 2012 these efforts resulted in
FDA approval of vismodegib, a potent orally administered SMO inhibitor for the treatment of locally advanced,
surgically inoperable and potentially fatal BCCs. Despite their undeniable efficacy, the utility of currently available
HH signaling inhibitors is hampered by rapid development of tumor resistance and tumor recurrence. While
uninhibited Hh signaling clearly drives BCC resistance and recurrence, many BCCs do not manifest SMO
mutations indicating involvement of additional tumorigenic mechanisms. We have discovered that vismodegib
resistance involves dysregulation of the bromodomain-containing proteins BRD7 and BRD9 of the
SWItch/Sucrose NonFermentable (SWI/SNF) nucleosome remodeling complexes. Utilizing genetically well-
defined in vitro and in vivo murine models of BCC, and patient-derived human BCC cells, our preliminary data
compellingly demonstrate that (i) HHi resistance is associated with global decreases in histone acetylation and
chromatin accessibility, and (ii) genetic ablation of BRD7 renders drug-naïve BCC cells resistant to HHi. Based
on our preliminary data, this application will test the hypothesis that the BRD7-BRD9 nexus drives HHi resistance
and that the BRD9 blockade prevents the emergence of HHi resistance. Aim 1 will probe the chromatin
modifications and gene expression signatures associated with HHi resistance, and their relevance to the BRD7-
BRD9 axis. Aim 2 will test in vivo consequences of genetic manipulation of the BRD7 and BRD9 nexus in
genetically-defined models (i.e., epidermis-specific deletions in BRD7 [Brd7 KO] or Akt1 [Akt1+/-]. Aim 3 will test
the potential utility of select BRD9 and Akt inhibitors for overcom...

## Key facts

- **NIH application ID:** 10771985
- **Project number:** 5R01ES030481-05
- **Recipient organization:** COLUMBIA UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** DAVID RINSEY BICKERS
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $364,500
- **Award type:** 5
- **Project period:** 2020-04-07 → 2025-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10771985

## Citation

> US National Institutes of Health, RePORTER application 10771985, Molecular Mechanisms Underlying the Prevention of BCC Resistance (5R01ES030481-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10771985. Licensed CC0.

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