# Novel Mechanisms Controlling SCLC Tumor Initiation

> **NIH NIH R21** · UNIVERSITY OF NEBRASKA MEDICAL CENTER · 2022 · $208,437

## Abstract

PROJECT SUMMARY / ABSTRACT
The goal of this project is to identify novel molecular determinants of small-cell lung carcinoma (SCLC)
preneoplastic development. Relatively little is known about the molecular mechanisms that initiate
preneoplasia in this highly aggressive, widely metastatic, and lethal lung cancer. Almost all patients with SCLC
are, or were, heavy smokers. Loss-of-function mutations in genes encoding the tumor suppressors TP53 and
Rb1 occur in almost all SCLC tumors. Moreover, TP53 and Rb1 have been shown recently to constrain the
self-renewal of pulmonary neuroendocrine cells (PNECs), which are a cell of origin for SCLC. Despite the
documentation of these and other genetic alterations essential to the molecular pathogenesis of SCLC, the
identification of effective therapeutic targets has been limited. Detection of key vulnerabilities unique to SCLC
would be a major advance toward eradicating deaths from lung cancer. One potential contributor to the
preneoplastic leading to SCLC development is the molecular scaffold Kinase Suppressor of Ras 2 (KSR2). Our
analysis reveals that the molecular scaffold KSR2 is undetectable in normal lung tissue but is robustly
expressed in PNECs and SCLC cell lines, predominantly those of the most common Achaete-scute complex
homolog 1 (ASCL1) subtype. The relevance of this correlation to the development and progression of
preneoplastic SCLC lesions is implied by previous observations that (1) ChIP-seq analysis revealed KSR2 as a
transcriptional target of ASCL1 in SCLC, and (2) that ASCL1 is essential for the development of normal lung
neuroendocrine cells and for the tumor-initiating capacity within SCLC. Similarly, KSR2 knockdown markedly
suppresses clonogenicity and self-renewal in highly tumorigenic SCLC subpopulations in vitro and in vivo.
These data suggest the hypothesis that KSR2 is essential for self-renewal and long-term propagation of a
foundational neuroendocrine population essential to SCLC formation, which will be tested by 1) determining
the role of KSR2 in PNEC and SCLC TPC self-renewal and SCLC tumor formation and 2) defining the KSR2-
mediated signaling pathways that support SCLC TPC self-renewal.

## Key facts

- **NIH application ID:** 10453763
- **Project number:** 5R21CA256638-02
- **Recipient organization:** UNIVERSITY OF NEBRASKA MEDICAL CENTER
- **Principal Investigator:** Robert E. Lewis
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $208,437
- **Award type:** 5
- **Project period:** 2021-08-01 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10453763

## Citation

> US National Institutes of Health, RePORTER application 10453763, Novel Mechanisms Controlling SCLC Tumor Initiation (5R21CA256638-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10453763. Licensed CC0.

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