# NEUROD1 function in SCLC fate and plasticity

> **NIH NIH R01** · DUKE UNIVERSITY · 2024 · $550,323

## Abstract

Small cell lung cancer (SCLC) is a highly aggressive neuroendocrine lung tumor responsible for > 30,000 deaths
annually in the US. SCLC has a two-year survival rate of ~6% with no approved targeted therapies beyond
recently-approved immunotherapy. SCLC is initially highly responsive to chemotherapy, but rapidly develops
resistance leading to mortality in ~12 months. A major unmet need for SCLC treatment is the identification of
new therapeutic targets and treatment strategies. SCLC has historically been treated as a single disease without
patient stratification based on molecular information. We and others recently identified distinct SCLC molecular
subtypes based on expression of lineage-related oncogenic transcription factors: ASCL1, NEUROD1, POU2F3
and more controversially, YAP1. MYCL oncogene is associated with the most common ASCL1 group (~70% of
SCLC), while MYC is overexpressed in the NEUROD1/POU2F3/YAP1 subtypes (~30% of SCLC). Importantly,
we and others found that MYC-driven SCLC has unique therapeutic vulnerabilities compared to MYCL-driven
SCLC. MYC has the capacity to drive SCLC subtype plasticity, promoting ASCL1+ tumors to a NEUROD1+ and
then a YAP1+ state. MYC-induced Notch pathway activation is critical for SCLC subtype plasticity. While ASCL1
has been frequently studied, much less is known about the 2nd-most common NEUROD1+-subtype. We
hypothesize that NEUROD1 expression denotes a neuronal transcriptional state of SCLC, that NEUROD1-
mediated repression of Notch signaling is critical for this tumor cell state, and that the NEUROD1+ state has
unique therapeutic vulnerabilities. We further predict that NEUROD1 inhibition will shift tumors to
developmentally predictable non-neuroendocrine cell fates. Our objective is to determine the function of
NEUROD1 in the NEUROD1+ subtype of SCLC, to identify mechanisms that regulate subtype plasticity, and
uncover the relationship between NEUROD1 and Notch signaling. Toward this end, we created the first mouse
model of NEUROD1+ SCLC and generated mice with conditional Neurod1 loss to study its function in vivo.
Preliminary data have identified highly conserved NEUROD1 target genes. Large-scale CRISPR-based genetic
screens have identified predicted dependencies that have the potential for therapeutic targeting. Our hypotheses
will be tested in two specific aims: 1) Determine the function of NEUROD1 in MYC-driven SCLC cell fate. 2)
Determine the mechanistic relationship between NEUROD1 and Notch signaling in SCLC subtype plasticity. Our
approach is innovative because we will employ novel immune-competent GEMMs of MYC-driven SCLC, ~17
new human PDX, and single cell data from primary human SCLC. We will use state-of-the-art technologies in
single cell RNA-seq and lineage tracing in new organoid models coupled with our ChIP-seq data to
comprehensively determine the role of NEUROD1 in SCLC. This research is significant because these findings
will lead to a better understanding of SCLC molecular subt...

## Key facts

- **NIH application ID:** 10904317
- **Project number:** 1R01CA262134-01A1
- **Recipient organization:** DUKE UNIVERSITY
- **Principal Investigator:** Trudy Gale Oliver
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $550,323
- **Award type:** 1
- **Project period:** 2024-04-01 → 2029-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10904317

## Citation

> US National Institutes of Health, RePORTER application 10904317, NEUROD1 function in SCLC fate and plasticity (1R01CA262134-01A1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10904317. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*