# Interrogating roles for REST in small cell lung cancer therapy response and resistance

> **NIH NIH R01** · FRED HUTCHINSON CANCER CENTER · 2024 · $582,076

## Abstract

SUMMARY
Small cell lung cancer (SCLC) is a lethal tumor type characterized by exquisite response to chemotherapy
followed by rapid emergence of chemoresistance. Addition of PDL-1 inhibition to platinum/etoposide
chemotherapy leads to improved clinical responses but only a small subset of SCLC patients benefit. Distinct
subsets of SCLC have been identified including high-neuroendocrine and low-neuroendocrine (NE) subtypes.
High-NE SCLC, expressing high levels of ASCL1 (SCLC-A) or NEUROD1 (SCLC-N) is best understood, with
genetically engineered mouse models available. However, our understanding of low-NE subtypes is poor, owing
in part to a lack of mouse models. A low-NE immune “inflamed” subset of SCLC (SCLC-I) exhibited increased
response to immune checkpoint blockade and high expression of RE-1 Silencing Element (REST), a suppressor
of neuronal and neuroendocrine gene expression. Aim 1 tests hypotheses that REST overexpression in a
mouse model of SCLC will result in low-NE SCLC and that REST increases immunogenicity. We will use gain
and loss of function studies to dissect the contribution of REST to SCLC and to model low-NE SCLC. RNA-seq
analyses will use data from mouse GEM models and isogenic cell lines with REST perturbation to identify genes
consistently regulated by REST while CUT&RUN will identify direct targets of REST. We will perform gain and
loss of function studies to assess pathways through which REST alters the biology of SCLC, with an initial focus
on how REST controls the expression of MHC-I. Aim 2 builds from our preliminary data that implicate REST
expression in driving chemotherapy resistance. We performed an in vivo functional CRISPR activation
(CRISPRa) screen to identify genes that switch chemosensitive patient derived xenograft (PDX) models to
become chemoresistant when overexpressed and among the top screen hits was REST. We will study the
impact of REST perturbation on chemotherapy response and will test our hypothesis that REST expression will
cause a switch to chemoresistance. We will perform immunohistochemistry and molecular analyses to
characterize the response of REST-perturbed PDX models to chemotherapy in vivo. With the increased
appreciation of low-NE SCLC but poor understanding of the underlying biology, it is critical that this important
subset of SCLC be modelled and understood. This proposal provides new in vivo GEM and PDX models of low-
NE SCLC, which are essential reagents to link biologically distinct SCLC subsets to the most promising
therapeutic approaches.

## Key facts

- **NIH application ID:** 10822088
- **Project number:** 1R01CA287573-01
- **Recipient organization:** FRED HUTCHINSON CANCER CENTER
- **Principal Investigator:** David MacPherson
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $582,076
- **Award type:** 1
- **Project period:** 2023-12-22 → 2028-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10822088

## Citation

> US National Institutes of Health, RePORTER application 10822088, Interrogating roles for REST in small cell lung cancer therapy response and resistance (1R01CA287573-01). Retrieved via AI Analytics 2026-06-01 from https://api.ai-analytics.org/grant/nih/10822088. Licensed CC0.

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