# Targeting Drug-Resistant Cancer Stem Cell Niches of Gastrointestinal Stromal Tumor

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2020 · $423,106

## Abstract

PROJECT SUMMARY/ABSTRACT
Gastrointestinal Stromal Tumor (GIST) is the most common sarcoma in the U.S. The treatment of GIST with
imatinib, a tyrosine kinase inhibitor (TKI), that targets the KIT oncogene, provides proof of principle for precision
oncology. We now understand that GISTs also occur due to mutations in PDGFRA, RAS/BRAF/NF1, SDHA-D,
as well as FGFR1 and ETV6-NTRK3 fusions. Thus, there are several GIST subtypes and many of these are
imatinib resistant. Imatinib markedly improves patient survival, but fails to cure GIST as many patients develop
recurrences ≈8-12 months after stopping imatinib. These recurrences raise the question as to whether GIST
persistence post-imatinib occurs via an unappreciated mechanism. We hypothesize that KITneg tumor cells, which
lack KIT protein expression, represent TKI-resistant GIST cancer stem cells (CSCs) based on our preliminary
data that: 1) human KIT mutant GIST cell lines possess KITneg cells that self-renew, form tumorspheres, and
have primary TKI-resistance; 2) both KIT and non-KIT mutant resected human GISTs possess KITneg cells and
have increased expression of stem cell genes following TKI therapy; and 3) these KITneg cells overexpress
druggable targets (i.e., Hedgehog, AMPK, NF-kB, and AXL) involved in CSC biology. In this project, we propose
to further characterize and target these KITneg GIST CSCs to overcome this previously unappreciated, and
clinically relevant, source of TKI-resistance using state-of-the-art experimental techniques and advanced
computational analysis methods. In Aim 1, we will define the molecular and functional properties of KITneg cells
to determine how they promote GIST growth and TKI resistance. We will determine the self-renewal and
differentiation potential of each putative CSC population following serial TKI treatments that parallel FDA-
approved therapies. We will then identify conserved proteins and pathways of isolated TKI-resistant KITneg and
KIThi cells. We will also determine common mechanisms of TKI-resistance amongst KITneg cells following serial
therapies. In Aim 2, we will characterize the CSC properties and molecular heterogeneity of KITneg cells from
primary KIT mutant and non-KIT mutant tumors. We will determine the inter-/intra-tumoral self-renewal,
differentiation, and tumorsphere formation for primary putative CSC populations from GISTs. Thus, we will
determine conserved pathways in putative CSCs from genomically diverse GISTs. In Aim 3, we will validate
druggable targets (e.g., Hedgehog, AMPK, NF-kB, and AXL) and exploit these pathways for eradication of KITneg
cells in vitro and in vivo. We will validate our findings with genetic approaches to determine if these targets are
required to maintain viability. This project will explore the commonalities and differences across TKI-treated and
genomically diverse GIST CSCs, which represent a novel target for overcoming disease persistence and TKI-
resistance. Our proposal will identify novel drug targets ...

## Key facts

- **NIH application ID:** 9917752
- **Project number:** 5R01CA226803-02
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** Jason Keith Sicklick
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $423,106
- **Award type:** 5
- **Project period:** 2019-06-01 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9917752

## Citation

> US National Institutes of Health, RePORTER application 9917752, Targeting Drug-Resistant Cancer Stem Cell Niches of Gastrointestinal Stromal Tumor (5R01CA226803-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9917752. Licensed CC0.

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