# Molecular control of tumor-initiating cells in Ras-driven cancers

> **NIH NIH F30** · UNIVERSITY OF NEBRASKA MEDICAL CENTER · 2024 · $38,965

## Abstract

Project Summary
Tumor Initiating Cells (TICs) are a subpopulation of tumor cells defined by their ability to self-renew and
regenerate the heterogeneous tumor. TICs have altered metabolic and drug efflux properties, allowing them to
persist as a sanctuary population of resistant cells during treatment. As such, TICs mediate tumor recurrence
and metastasis, which are key contributors to mortality. To date, however, there are no therapies targeting the
TIC population in solid tumors. My data show that the formation and maintenance of TICs in Ras-driven
colorectal and lung tumor cell lines are critically dependent on the molecular scaffold Kinase Suppressor of
Ras 1 (KSR1). KSR1 coordinates signaling through the Raf-MEK-ERK cascade downstream of oncogenic Ras.
KSR1 is necessary for Ras-driven tumor formation, but dispensable for normal cell growth. Moreover, ksr1-/-
mice are phenotypically normal but resistant to cancer formation. These characteristics highlight the value of
KSR1 as a potential therapeutic target. Our data further show that KSR1 KO can prevent MEK inhibitor
trametinib-mediated expansion of the TIC population and restore sensitivity to trametinib in both NSCLC and in
CRC where resistance currently limits clinical utility of this drug. Further characterization using KSR1
transgenes with defined mutations in downstream effector-binding regions has identified KSR1 interaction with
both ERK and AMPK to be implicated in maintenance of the TIC population, in vitro clonogenicity, and
resistance to trametinib. These data suggest the hypothesis that KSR1-dependent ERK and AMPK activation
in Ras-driven cancers plays a selective role in the formation of tumor-initiating cells and the drug resistance
conveyed by this subpopulation. I will test this hypothesis by 1) defining the proximal KSR1-dependent
signaling pathways that control TICs and trametinib resistance; and 2) assessing the ability of targeted KSR1
degradation to impair tumor-initiating capacity in a preclinical tumor organoid model. Completion of these aims
will expand mechanistic understanding of Ras-driven TIC formation and maintenance and may reveal a novel
therapeutic approach to treat TIC-mediated resistance, recurrence, and metastasis.

## Key facts

- **NIH application ID:** 10877707
- **Project number:** 5F30CA268766-02
- **Recipient organization:** UNIVERSITY OF NEBRASKA MEDICAL CENTER
- **Principal Investigator:** Heidi Vieira
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $38,965
- **Award type:** 5
- **Project period:** 2023-07-01 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10877707

## Citation

> US National Institutes of Health, RePORTER application 10877707, Molecular control of tumor-initiating cells in Ras-driven cancers (5F30CA268766-02). Retrieved via MORVS 2026-10-25 from https://api.morvs.ai/grant/nih/10877707. Licensed CC0.

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