# Genomic and Functional Identification of Chemotherapy Resistance Mechanisms in Small Cell Lung Cancer

> **NIH NIH U01** · WASHINGTON UNIVERSITY · 2020 · $778,924

## Abstract

Project Summary
Small cell lung cancer (SCLC) is responsible for over 30,000 deaths each year in the United States alone.
SCLC has a two-year survival rate of ~6% and unlike the other major subtypes of lung cancer, there are
currently no targeted therapies approved for SCLC. SCLC is initially highly responsive to chemotherapy, but
rapidly develops resistance leading to mortality in ~10 months. Clearly, a major unmet need for the treatment
of SCLC is the identification of new therapeutic targets and treatment strategies to combat chemo-resistant
disease. Our understanding of chemotherapy resistance mechanisms has been hampered by a lack of
relapsed human SCLC tissue due to rare surgical resections. In addition, there have been few mouse models
of the disease that exhibit short latencies and chemo-sensitivity. To address these challenges, we performed
whole exome sequencing on relapsed SCLC from 30 patients. Relapse-specific genomic alterations in the
WNT/APC/β-catenin pathway were identified in ~66% of relapsed SCLC suggesting that this pathway
promotes chemo-resistance. Second, we developed a novel mouse model of SCLC driven by loss of Rb1,
Trp53 and overexpression of Myc—three of the most common genetic alterations in the human disease. Mice
develop SCLC within weeks that highly resembles the human disease at the level of histopathology, biomarker
expression and chemo-sensitivity followed by relapse. This model will be a useful tool to test candidate
chemotherapy resistance mechanisms and identify novel therapeutic targets that inhibit chemo-resistance. The
objective of this study is to use this novel mouse model and comprehensive genomic analyses of primary and
relapsed human SCLC to identify mechanisms of chemotherapy resistance and novel therapeutic targets to
combat chemo-resistant disease. We hypothesize that activation of the WNT/β-catenin pathway promotes
chemo-resistance in SCLC and that targeted inhibition of the pathway will inhibit chemo-resistant disease. We
predict that expansion of our genomic and transcriptomic profiling will identify additional novel pathways
involved in chemo-resistance. To test these hypotheses, we will: 1) identify recurrent pathway alterations in
relapsed human and mouse SCLC using whole genome, exome, transcriptome and epigenome sequencing
and 2) functionally determine whether canonical WNT/β-catenin signaling and other candidate pathways are
necessary and sufficient for chemo-resistance in SCLC in vivo. This approach is innovative because we will
employ unbiased comprehensive genomic and epigenomic analyses on relapsed human SCLC and a novel
immune-competent mouse model of SCLC that recapitulates key features of the human disease. The WNT/β-
catenin pathway is largely unexplored in SCLC. This research is significant because there are currently no
targeted therapies approved for SCLC. A better understanding of the critical pathways driving chemo-
resistance in SCLC will impact the treatment and survival of p...

## Key facts

- **NIH application ID:** 10002189
- **Project number:** 5U01CA231844-03
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Ramaswamy Govindan
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $778,924
- **Award type:** 5
- **Project period:** 2018-09-01 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10002189

## Citation

> US National Institutes of Health, RePORTER application 10002189, Genomic and Functional Identification of Chemotherapy Resistance Mechanisms in Small Cell Lung Cancer (5U01CA231844-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10002189. Licensed CC0.

---

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