# Progression, response, and resistance of RSPO fusion colorectal cancer

> **NIH NIH R01** · WEILL MEDICAL COLL OF CORNELL UNIV · 2022 · $376,511

## Abstract

PROJECT SUMMARY
Colorectal cancer (CRC) is the second leading cause of cancer-related death in the Western world, and there
are no effective therapies for patients with advanced disease. Large chromosome rearrangements involving
two members of the RSPO family of WNT pathway co-agonists were recently described in 5-10% of human
CRC, and offer a potential target to treat this subset of patients. However, we still do not fully understand how
specific RSPO fusion proteins (e.g. PTPRK-RSPO3) contribute to tumorigenesis, and whether targeting this
genomic change will provide meaningful therapeutic responses and improved patient outcomes. To begin to
delineate the consequences of RSPO fusions, we developed genetically engineered animal models in which
endogenous chromosome rearrangements can be generated in the intestine using an inducible CRISPR/Cas9
platform we pioneered. Using this approach, we provided the first evidence that Ptprk-Rspo3 chromosome
rearrangements are sufficient to initiate tumor development in the gut. Moreover, tumors derived from
endogenous chromosome alterations produce phenotypes distinct from published models that induce ectopic
overexpression of an Rspo3 cDNA. Thus, defining the molecular consequences of specific fusion events is
likely critical for understanding the true impact of such rearrangements on tumor biology. In addition, we
showed that Ptprk-Rspo3 fusion lesions growing within the native intestinal mucosa are exquisitely sensitive to
drugs that block WNT secretion, but that the accumulation of genetic alterations can influence drug response.
Based on this work, we will test the hypothesis that Ptprk-Rspo3 fusion proteins provide a WNT-dependent cell
intrinsic growth advantage due to the endogenous fusion event, but that the accumulation of cooperating
oncogenic insults promotes WNT independence and drug resistance.
Using ex vivo organoid model systems, Aim 1 will determine the molecular consequences of specific RSPO
fusions and delineate how specific fusion events and loss of the fusion partner (PTPRK) promote cell
transformation. In Aim 2, through sequential CRISPR-based editing in organoids and orthotopic tumor models,
we will define genetic landscape and molecular mechanisms linked to therapy failure and acquired drug
resistance. Together, this work will contribute significantly to a molecular understanding of how RSPO genomic
rearrangements impact oncogenic WNT signaling, and has the potential to make an immediate and significant
clinical contribution, by defining the mechanisms that influence tumor progression and therapy resistance.
We expect our studies will reveal ways to more effectively identify patient populations that would respond to
treatment and/or predict combination and second line therapies for treatment refractory tumors. Thus, results
from this study will be a significant step toward the overall goal of safe and effective targeted therapies for
CRC, and improved patient outcomes.

## Key facts

- **NIH application ID:** 10456079
- **Project number:** 5R01CA222517-05
- **Recipient organization:** WEILL MEDICAL COLL OF CORNELL UNIV
- **Principal Investigator:** LUKAS Edward DOW
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $376,511
- **Award type:** 5
- **Project period:** 2018-08-01 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10456079

## Citation

> US National Institutes of Health, RePORTER application 10456079, Progression, response, and resistance of RSPO fusion colorectal cancer (5R01CA222517-05). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10456079. Licensed CC0.

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