# Dihydroceramide desaturase (DES1) as a mediator of receptor tyrosine kinase-driven metastasis in breast cancer

> **NIH NIH R01** · STATE UNIVERSITY NEW YORK STONY BROOK · 2021 · $361,779

## Abstract

ABSTRACT
Despite improvements in treatment, clinical outcomes for late stage breast cancer (BC) remain poor and there
is a critical need for new therapies for metastatic disease. Hyperactivation of receptor tyrosine kinase (RTK)
signaling in BC is associated with poor prognosis yet direct RTK inhibitors have had mixed results in clinical
trials. RTK signaling drives anoikis resistance, a key metastasis-enabling biology. Thus, defining the underlying
mechanisms of this process could identify new druggable targets to treat metastasis. Sphingolipids (SL) are a
family of bioactive lipids, classically implicated in cell death, and whose metabolism is altered in cancer.
Ongoing studies from the PI’s group, using HER2 amplification as a model system of RTK signaling have
identified the SL enzyme dihydroceramide desaturase 1 (DES1) as a key HER2-regulated node in the SL
network that was required for anoikis resistance of HER2+ BC cells. In clinical data, high DES1 levels were
associated with worse outcomes in HER2+ BC. Moreover, increasing DES1 levels was sufficient to drive in
vitro tumorigenicity of HER2+ BC cells whereas DES1 KO reduced in vivo metastasis. Taken together, these
novel data have led us to the central hypothesis that DES1 is necessary and sufficient to promote RTK-
driven anoikis resistance and metastasis which will be tested by pursuing three specific aims. The first aim
will define the role of DES1 in RTK-driven anoikis resistance in vitro and in vivo using Crispr/Cas9
technology to knockout DES1 in RTK-driven BC cells and defining biological effects on in vitro tumorigenicity
and in vivo cell survival in the circulation. The second aim will define the mechanism(s) by which RTKs
regulate and maintains DES1 activity following ECM detachment using gain of function and loss of
function approaches to directly connect DES1 with oncogenic activation of PI3K signaling and the pentose
phosphate pathway. The third aim will establish DES1 as a driver of in vivo metastasis and
chemoresistance in BC harboring RTK hyperactivation using gain of function approaches to show that
increased DES1 is sufficient to promote an aggressive phenotype in RTK-activated BC and can mediate
resistance to the targeted HER2 therapy lapatinib. Collectively, these studies will establish DES1 as a key
effector of oncogenic RTK signaling and as a novel druggable target, effective at overcoming anoikis
resistance and useful for treatment of metastatic BC.

## Key facts

- **NIH application ID:** 10119000
- **Project number:** 1R01CA248014-01A1
- **Recipient organization:** STATE UNIVERSITY NEW YORK STONY BROOK
- **Principal Investigator:** Christopher James Clarke
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $361,779
- **Award type:** 1
- **Project period:** 2021-03-03 → 2026-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10119000

## Citation

> US National Institutes of Health, RePORTER application 10119000, Dihydroceramide desaturase (DES1) as a mediator of receptor tyrosine kinase-driven metastasis in breast cancer (1R01CA248014-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10119000. Licensed CC0.

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