Not All Wnt Activation Is Equal: Ligand-Dependent versus Ligand-Independent Wnt Activation in Colorectal Cancer

SIMPLE SUMMARY: Colorectal cancer is the third most common cause of cancer-related deaths. The Wnt signaling pathway is activated by genetic mutations in most patients with colorectal cancer. A number of different types of Wnt pathway mutation have been described: some increase the sensitivity of tumor cells to Wnt ligands produced by stromal cells (ligand-dependent), while others drive downstream activation of the pathway (ligand-independent). Ligand-dependent tumors are of particular interest as there are a number of emerging treatment options, such as porcupine inhibitors, that can specifically target these tumors. In this review, we discuss what is known about these different types of Wnt activating mutations. We propose that ligand-dependent tumors should be viewed as a separate subset of colorectal cancer with its own biomarkers, prognosis and targeted therapies. ABSTRACT: Wnt signaling is ubiquitously activated in colorectal tumors and driver mutations are identified in genes such as APC, CTNNB1, RNF43 and R-spondin (RSPO2/3). Adenomatous polyposis coli (APC) and CTNNB1 mutations lead to downstream constitutive activation (ligand-independent), while RNF43 and RSPO mutations require exogenous Wnt ligand to activate signaling (ligand-dependent). Here, we present evidence that these mutations are not equivalent and that ligand-dependent and ligand-independent tumors differ in terms of underlying Wnt biology, molecular pathogenesis, morphology and prognosis. These non-overlapping characteristics can be harnessed to develop biomarkers and targeted treatments for ligand-dependent tumors, including porcupine inhibitors, anti-RSPO3 antibodies and asparaginase. There is emerging evidence that these therapies may synergize with immunotherapy in ligand-dependent tumors. In summary, we propose that ligand-dependent tumors are an underappreciated separate disease entity in colorectal cancer.