Exploiting the Therapeutic Interaction of WNT Pathway Activation and Asparaginase for Colorectal Cancer Therapy
Abstract
Colorectal cancer is driven by mutations that activate canonical WNT/β-catenin signaling, but inhibiting WNT has significant on-target toxicity, and there are no approved therapies targeting dominant oncogenic drivers. We recently found that activating a β-catenin–independent branch of WNT signaling that inhibits GSK3-dependent protein degradation induces asparaginase sensitivity in drug-resistant leukemias. To test predictions from our model, we turned to colorectal cancer because these cancers can have WNT-activating mutations that function either upstream (i.e., R-spondin fusions) or downstream (APC or β-catenin mutations) of GSK3, thus allowing WNT/β-catenin and WNT-induced asparaginase sensitivity to be unlinked genetically. We found that asparaginase had little efficacy in APC or β-catenin–mutant colorectal cancer, but was profoundly toxic in the setting of R-spondin fusions. Pharmacologic GSK3α inhibition was sufficient for asparaginase sensitization in APC or β-catenin–mutant colorectal cancer, but not in normal intestinal progenitors. Our findings demonstrate that WNT-induced therapeutic vulnerabilities can be exploited for colorectal cancer therapy.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Nov 01, 2020
- Source ID
- 10.1158/2159-8290.cd-19-1472
Entities
People
- Alejandro Gutierrez
- Chen Yuan
- Connor McGuckin
- Emma M Schatoff
- Ewa Sicinska
- Florence Wagner
- James Degar
- Joshua R. Sacher
- Kimmie Ng
- Laura Hinze
- Lukas E Dow
- Marios Giannakis
- Martin Stanulla
- Roxane Labrosse
- Sabine Schreek
- Salmaan Karim
- Teng Han
Organizations
- Cancer Research UK
- Dana–Farber Cancer Institute
- Hannover Medical School
- Harvard Medical School
- National Cancer Institute
- National Institute of General Medical Sciences
- National Institutes of Health
- Stand Up to Cancer
- United States Department of Defense
- Weill Cornell Medicine