# Identifying and understanding drivers of chemoresistance in small cell lung cancer

> **NIH NIH R01** · FRED HUTCHINSON CANCER CENTER · 2024 · $503,547

## Abstract

SUMMARY
Small cell lung cancer (SCLC) is an aggressive and lethal neuroendocrine lung cancer type. Most patients initially
respond to chemotherapy but relapse occurs within months and genetic alterations that drive chemoresistance
are poorly understood. Beyond amplification of MYC family members and epigenetic silencing of SLFN11, the
field has an extremely poor understanding of genes that promote SCLC chemoresistance. We developed a novel
system in which we genetically alter highly chemosensitive patient derived xenograft (PDX) models of SCLC to
identify perturbations that confer resistance to cisplatin/etoposide (CIS-ETO) in vivo. Lentiviral overexpression
of either MYCN or MYCL caused complete switch to chemoresistance (Grunblatt et al, 2020). To systematically
identify SCLC chemoresistance drivers, we expanded use of this PDX lentiviral transduction system to perform
in vivo CRISPR inactivation screens. We identified sgRNAs targeting multiple components of the SAGA (Spt-
Ada-Gcn5 acetyltransferase) chromatin modifying complex as screen hits and confirmed that deleting the SAGA
member USP22, a deubiquitylase, indeed confers chemoresistance in two SCLC PDX models, while return of
USP22 to a USP22-null SCLC PDX model re-sensitizes to chemotherapy. Our overarching hypothesis is that
suppressing the expression of USP22 and SAGA complex members drives chemoresistance in SCLC, and that
transcriptional changes caused by SAGA suppression are critical. Aim 1, we will interrogate how genetically
perturbing multiple SAGA complex members, including USP22 and TADA1, in PDX models alters the in vivo
response to chemotherapy. Aim 2 employs genomic and proteomic approaches to develop a deep molecular
understanding of the USP22-regulated genes and pathways that contribute to chemotherapy response in SCLC
and uses human patient data to prioritize key SAGA targets for functional study. Decades of studying
chemotherapy response in SCLC cell lines grown in vitro have provided little insight into how chemoresistance
emerges, suggesting that key aspects of this process are not recapitulated under tissue culture conditions. Our
novel system prioritizes the study of chemoresistance using in vivo approaches with potential to provide
foundational knowledge to help prevent chemoresistance or re-sensitize chemoresistant SCLC to chemotherapy.

## Key facts

- **NIH application ID:** 10880359
- **Project number:** 5R01CA281133-02
- **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:** $503,547
- **Award type:** 5
- **Project period:** 2023-07-01 → 2028-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10880359

## Citation

> US National Institutes of Health, RePORTER application 10880359, Identifying and understanding drivers of chemoresistance in small cell lung cancer (5R01CA281133-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10880359. Licensed CC0.

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