{"doi":"10.1158/2159-8290.cd-19-1472","title":"Exploiting the Therapeutic Interaction of WNT Pathway Activation and Asparaginase for Colorectal Cancer Therapy","abstract":"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. Significance: Solid tumors are thought to be asparaginase-resistant via de novo asparagine synthesis. In leukemia, GSK3α-dependent protein degradation, a catabolic amino acid source, mediates asparaginase resistance. We found that asparaginase is profoundly toxic to colorectal cancers with WNT-activating mutations that inhibit GSK3. Aberrant WNT activation can provide a therapeutic vulnerability in colorectal cancer. See related commentary by Davidsen and Sullivan, p. 1632. This article is highlighted in the In This Issue feature, p. 1611","journal":"Cancer Discovery","year":2020,"id":60599,"datarank":0.62147020895873,"base_score":4.143134726391533,"endowment":4.143134726391533,"self_citation_contribution":0.62147020895873,"citation_network_contribution":0.0,"self_endowment_contribution":0.62147020895873,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":62,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9511,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":320159,"name":"Roxane Labrosse","orcid":"0000-0003-3448-2098","position":1,"is_corresponding":false},{"id":320160,"name":"James Degar","orcid":"0000-0002-5387-9069","position":2,"is_corresponding":false},{"id":237942,"name":"Teng Han","orcid":"0000-0001-8857-8787","position":3,"is_corresponding":false},{"id":263586,"name":"Emma M. Schatoff","orcid":"0000-0002-7327-1843","position":4,"is_corresponding":false},{"id":321845,"name":"Sabine Schreek","orcid":null,"position":5,"is_corresponding":false},{"id":320161,"name":"Salmaan Karim","orcid":"0000-0002-8742-4257","position":6,"is_corresponding":false},{"id":320162,"name":"Connor McGuckin","orcid":"0000-0001-8860-9926","position":7,"is_corresponding":false},{"id":320163,"name":"Joshua R. Sacher","orcid":"0000-0003-4381-3979","position":8,"is_corresponding":false},{"id":264528,"name":"Florence F. Wagner","orcid":"0000-0001-8981-0330","position":9,"is_corresponding":false},{"id":320164,"name":"Martin Stanulla","orcid":"0000-0002-3834-0727","position":10,"is_corresponding":false},{"id":56399,"name":"Chen Yuan","orcid":"0000-0002-0708-9648","position":11,"is_corresponding":false},{"id":310590,"name":"Ewa Sicińska","orcid":"0000-0001-7187-319X","position":12,"is_corresponding":false},{"id":3011,"name":"Marios Giannakis","orcid":"0000-0001-9012-6982","position":13,"is_corresponding":false},{"id":3730,"name":"Kimmie Ng","orcid":"0000-0003-0631-1494","position":14,"is_corresponding":false},{"id":237945,"name":"Lukas E. Dow","orcid":"0000-0001-7048-1418","position":15,"is_corresponding":false},{"id":320165,"name":"Alejandro Gutiérrez","orcid":"0000-0002-0249-9007","position":16,"is_corresponding":false},{"id":321844,"name":"Laura Hinze","orcid":null,"position":0,"is_corresponding":true}],"reference_count":78,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-18T21:09:05.493770Z","pmid":"32703769","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}