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 sig naling, but inhibiting WNT has signifi cant on-target toxicity, and there are no approved therapies targeting dominant oncogenic drivers. We recently found that activating a β -cateninindependent 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 effi cacy in APC or β -catenin-mutant colorectal cancer, but was profoundly toxic in the setting of R-spondin fusions. Pharmacologic GSK3 α inhibition was suffi cient for asparaginase sensitization in APC or β -catenin-mutant colorectal cancer, but not in normal intestinal progenitors. Our fi ndings demonstrate that WNT-induced therapeutic vulnerabilities can be exploited for colorectal cancer therapy.

Asparagine: A Metabolite to Be Targeted in Cancers

“…Similar to findings in leukemic blasts, the synergy between L-asparaginase and WNT pathway activation can also be observed in solid tumors. Similar to ALL cells, the same group found that WNT activation by R-spondin fusion in colorectal cancers drives selective sensitivity to L-asparaginase treatment [ 80 ]. Of interest, APC mutations that activate beta-catenin downstream of GSK3 shows little response to L-asparaginase treatment.…”

Patient-derived tumor models: a more suitable tool for pre-clinical studies in colorectal cancer

“…Similarly, by candidate-gene or comprehensive genomic analyses, other actionable targets were identified as cetuximab-resistance biomarkers, including MET Proto-Oncogene and Fibroblast Growth Factor Receptor 1 ( FGFR1 ) amplification [ 46 , 96 ], ERBB2 and MAP2K1 activating mutations [ 46 , 97 ], insulin Like Growth Factor 2 ( IGF2 ) overexpression [ 98 ], and the fusion of echinoderm microtubule-associated protein-like 4 ( EML4 ) gene with the anaplastic lymphoma kinase ( ALK ) gene leading to the production of a protein (EML4-ALK) that promotes and maintains the malignant behavior of the cancer cells [ 99 ]. More empirically, Hinze and colleagues showed that CRC PDXs displayed significant tumor responses upon Glycogen Synthase Kinase 3 α (GSK3α) inhibition combined with the anti-leukemic enzyme asparaginase [ 100 ]. However, further studies are required before the translation of such results into viable therapeutic approaches.…”

Wnt/β‐catenin signaling: Structure, assembly and endocytosis of the signalosome

“…Due to this fact, these cancers become refractory to treatments with asparaginase, an enzyme that deaminates and depletes endogenous asparagine and has been long known for its therapeutic use against lymphomas (Broome, 1963a(Broome, , 1963bRizzari et al, 2013). However, recent studies have shown that forced activation of the Wnt/STOP pathway, for example by chemical inhibition of GSK3, impairs the ability of malignant cells to utilize protein degradation to obtain asparagine and sensitize them to asparaginase treatments (Hinze et al, ,2019(Hinze et al, , , 2020. Importantly, the combined treatment of asparaginase and GSK3-specific inhibitors eliminates leukemic or colorectal cancer cells in mouse models, without affecting noncancerous cells.…”