# Kinase Signaling in Epidermal Homeostasis and Early Neoplasia

> **NIH NIH R01** · STANFORD UNIVERSITY · 2024 · $479,217

## Abstract

PROJECT SUMMARY
Kinases are essential to development and deregulation of their activity contributes to cancer
progression in multiple human malignancies. We recently demonstrated that the receptor tyrosine
kinase rearranged during transfection (RET) enforces the undifferentiated state in epidermal
progenitor cells and is aberrantly activated in cutaneous squamous cell carcinoma (cSCC). Our
long-term goal is to help develop topical selective RET inhibitors for effective therapeutic
prevention of cSCC. The overall objectives of this proposal are to (i) elucidate the molecular
mechanism(s) of RET regulation in human epidermis and (ii) define RET-regulated impacts on
the tumor immune microenvironment while demonstrating the therapeutic efficacy of targeting
RET for cSCC prevention. Our central hypothesis is that sustained expression of RET is an early
and actionable event in cSCC development that results from disruption of E3 ligase interaction,
enabling deregulation of downstream kinases and promoting immune escape through
downregulation of MHC expression. The rationale for this project is that a determination of RET
regulation and activation in the epidermis will create a strong conceptual framework for
development of therapeutic strategies aimed at controlling RET signaling, such as inhibiting RET
for effective secondary prevention of cSCC in at-risk persons. In the first Aim of our proposal, we
will test the central hypothesis by characterizing the RET-Siah1 interaction and defining the key
downstream branches regulated by epidermal RET. In the second Aim, we will investigate the
timing and consequences of RET activation during the progression of human cSCC from normal
skin to carcinoma in situ and evaluate the efficacy of targeting RET through genetic ablation or
pharmacologic inhibition on photocarcinogenesis in vivo. The research proposed in this
application is innovative, in our opinion, because it focuses on inhibiting a novel molecular target
to therapeutically restore terminal maturation as a means of skin cancer prevention. The proposed
research is significant because it is expected to justify preclinical and clinical studies on RET
inhibition for secondary prevention of cSCC. Ultimately, such knowledge has the potential to
reduce the incidence of skin cancer in this country.

## Key facts

- **NIH application ID:** 10979726
- **Project number:** 1R01CA286612-01A1
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** Carolyn S. Lee
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $479,217
- **Award type:** 1
- **Project period:** 2024-08-01 → 2025-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10979726

## Citation

> US National Institutes of Health, RePORTER application 10979726, Kinase Signaling in Epidermal Homeostasis and Early Neoplasia (1R01CA286612-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10979726. Licensed CC0.

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