# The role of Dclk1 in the initiation of colorectal cancer

> **NIH NIH R01** · UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR · 2021 · $338,550

## Abstract

Colorectal cancer (CRC) is the 3rd leading cause of cancer death in the U.S, and it is a necessity to
develop better drugs for those with advanced disease. Specific markers of CRC tumor stem cells (TSCs) have
been elusive for many years, but recently strong data has emerged to support the TSC-role originally proposed
by our lab for doublecortin-like kinase 1 (DCLK1) in APC mutant CRC. Specifically, Dclk1+ tuft cells initiate
tumorigenesis in response to Apc mutation as demonstrated by lineage tracing in the ApcMin/+ model of
intestinal neoplasia as well as in a model of inflammation-induced colon cancer. Strikingly, in the ApcMin/+
model, diphtheria toxin-inducible deletion of Dclk1+ cells results in a complete collapse of tumors with no
apparent negative effects.
While, APC is considered a gatekeeper in colorectal tumorigenesis and inactivating mutations exist in 34-70%
of CRC tumors, KRAS mutations are also exceptionally common (30-60%) and associated with
significantly decreased overall survival, particularly in metastatic disease. In addition to limiting therapeutic
options for CRC patients, KRAS mutations accompanied by APC loss strongly increase tumorigenesis,
metastasis, and TSC properties. The DCLK1+ cell is now strongly implicated as a cell-of-origin for KRAS-
driven pancreatic cancer, and recent proteomic studies demonstrate that knock-in of KRASG12/G13 mutations
into CRC cells results in specific DCLK1 upregulation20. Moreover, DCLK1 is highly expressed in CRC
metastases and predicts significantly decreased survival in patients. We propose to unravel DCLK1's role in
KRAS-mutant CRC progression and assess DCLK1-targeted therapies with the following Specific Aims:
Aim 1: Determine the role of DCLK1 and the DCLK1+ tuft cell in the initiation and progression of KRAS-mutant
colorectal cancer.
Aim 2: Dissect DCLK1's mechanistic role in CRC downstream of KRASG12D and in the background of APC
loss.
Aim 3: Demonstrate the feasibility of targeting DCLK1 in KRAS-mutant patient-derived CRC models as a
primary therapy and to overcome resistance to EGFR-targeted cetuximab and gefitinib.
These studies will utilize novel models to provide the first definitive assessment of the DCLK1's functional
significance in KRAS-driven CRC and its potential as both a primary therapeutic target and an adjuvant to
reverse KRAS-mediated resistance to EGFR inhibitors. We will pursue these studies with a highly multi-
disciplinary team of experts including: Courtney Houchen and Dongfeng Qu (DCLK1/gastrointestinal cancers),
Timothy Wang (DCLK1 mouse model), Channing Der (KRAS), Robert Langer (bioengineering), Hans Clevers
(CRC organoids), Min Li (mouse surgery models), and Magdalena Bieniasz (patient-derived xenografts).
These studies may lead to novel and effective therapies for patients with advanced CRC.

## Key facts

- **NIH application ID:** 10183185
- **Project number:** 5R01CA214017-05
- **Recipient organization:** UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
- **Principal Investigator:** Courtney Wayne Houchen
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $338,550
- **Award type:** 5
- **Project period:** 2017-06-15 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10183185

## Citation

> US National Institutes of Health, RePORTER application 10183185, The role of Dclk1 in the initiation of colorectal cancer (5R01CA214017-05). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10183185. Licensed CC0.

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