# Phosphorylation of ASCL1 to disrupt oncogenic activity in SCLC

> **NIH NIH F30** · UT SOUTHWESTERN MEDICAL CENTER · 2021 · $17,180

## Abstract

Small cell lung cancer (SCLC) is an aggressive neuroendocrine cancer that accounts for approximately 16% of
new lung cancer diagnoses. Though SCLC is initially responsive to cytotoxic chemotherapy, resistance quickly
develops, with 5-year survival rates below 7%, a prognosis that has not improved significantly over the past 30
years. ASCL1 is present in a majority of human-derived SCLC cell lines and, where tested, is required for
tumor cell growth. This proneural basic helix-loop-helix (bHLH) transcription factor normally regulates neuronal
differentiation during embryonic development. Its requirement in SCLC suggests that strategies to inhibit the
function of this transcription factor may represent a novel, targeted SCLC therapy. Proneural bHLH
transcription factors, including ASCL1, have a defined lifetime during embryonic development. It has been
proposed that proneural bHLH transcription factors are regulated by phosphorylation of a serine residue at a
conserved position within the bHLH domain. Phosphorylation at this site has been suggested to function as a
switch that rapidly shuts off the activity of ASCL1, overcoming an autoregulatory positive feedback loop that
sustains the proliferative capacity of ASCL1 expressing cells. Interestingly, ASCL1 does not appear to be
phosphorylated at this site in SCLC. I hypothesize that the phosphorylation of ASCL1 at this conserved
site can be induced to inactivate this oncogenic driver in the context of SCLC. The current proposal will
test this hypothesis by determining the effect of phosphorylation at this conserved site on the transcriptional
activity, DNA binding, and heterodimerization capacity of ASCL1. In addition, I will test whether
phosphorylation of ASCL1 at this conserved site can be invoked in SCLC to inhibit tumor growth by replacing
wild-type ASCL1 with phosphomimetic variants both in vitro and in vivo. Finally, in vitro phosphorylation assays
will be performed with several kinases predicted to phosphorylate ASCL1 at this site, to test the ability of
candidate kinase agonists to disrupt SCLC growth both in vitro and in vivo. These experiments have the
potential to identify a novel, mechanism-based therapy for this treatment resistant cancer.

## Key facts

- **NIH application ID:** 10061566
- **Project number:** 5F30CA228314-03
- **Recipient organization:** UT SOUTHWESTERN MEDICAL CENTER
- **Principal Investigator:** Demetra Patricia Kelenis
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $17,180
- **Award type:** 5
- **Project period:** 2018-12-03 → 2021-05-12

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10061566

## Citation

> US National Institutes of Health, RePORTER application 10061566, Phosphorylation of ASCL1 to disrupt oncogenic activity in SCLC (5F30CA228314-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10061566. Licensed CC0.

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