# Phosphorylation-dependent regulation of GLI transcription factors

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA-IRVINE · 2020 · $316,866

## Abstract

Project Summary
Basal cell carcinomas (BCCs) are locally invasive epithelial cancers that affect over 4 million patients a year in
the United States and are solely driven by activating mutations in the Hedgehog (HH) pathway. Inappropriate
HH pathway activation also drives growth of a variety of cancers including brain, pancreatic, prostate, and
small cell lung cancer that account for up to 25% of all human cancer deaths. HH antagonists such as
vismodegib are FDA-approved to treat advanced and metastatic BCCs, however, nearly 60% of advanced
tumors display inherent vismodegib resistance and 20% of tumors that do respond acquire drug resistance
every year. This is a highly relevant issue as advanced BCC cases are estimated to approach 400,000 patients
each year, illustrating a critical need to identify therapeutic targets downstream of SMO to suppress HH
pathway activity. The consequence of not meeting this need will likely be the inability to treat patients who are
resistant to current approved therapies, leading to an increase in mortality for patients inflicted with BCC and
other HH-dependent cancers.
Our long-term objective is to identify and develop targeted therapeutics to treat drug-resistant HH-driven
cancers. The overall objective of this application is to define how GLI is oncogenically activated in HH-driven
cancer. Our central hypothesis is that GLI phosphorylation drives transcriptional activation and SMO
antagonist-resistant BCC growth, and targeting the signaling pathways that activate GLI will suppress tumor
growth. My two specific aims will define 1) how GLI zinc finger phosphorylation and 2) how clinically recurrent
GLI mutations promote transcriptional activity, tumor growth, and drug resistance. Defining how GLI is
activated in cancer may reveal novel therapeutic targets to treat patients with HH-driven cancers.
To achieve these aims, we will use BCC cell lines and allografts that overexpress clinically observed and
recurrent GLI mutants to assay for tumor growth in the presence or absence of HH antagonists. We will use
the GLI mutants that show increased transcriptional activity to define how GLI is activated in cancer using
standard molecular biology, biochemistry, cell biology, and genetic techniques. Our preliminary data has
already identified three kinases that regulate GLI activity, and we plan to generate phospho-specific mutants to
define when, where, and how each kinase acts on GLI. We will immunofluorescently stain human tumors with
appropriate antibodies to verify these pathways operate in humans, and we will perform standard gain- and
loss-of-function studies to analyze the pathways involved over the lifetime of the tumor.

## Key facts

- **NIH application ID:** 9913480
- **Project number:** 5R01CA237563-02
- **Recipient organization:** UNIVERSITY OF CALIFORNIA-IRVINE
- **Principal Investigator:** Scott Atwood
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $316,866
- **Award type:** 5
- **Project period:** 2019-04-11 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9913480

## Citation

> US National Institutes of Health, RePORTER application 9913480, Phosphorylation-dependent regulation of GLI transcription factors (5R01CA237563-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9913480. Licensed CC0.

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