Protein Kinase C at the Crossroad of Mutations, Cancer, Targeted Therapy and Immune Response

SIMPLE SUMMARY: This review aims to analyze the clinical drawbacks faced by PKC inhibitors and uncovering aspects that might potentially interfere with the clinical outcome of compounds targeting PKC. In-depth analyses of the impact of key PKC mutations, the failures and promises of clinical trials conducted over the years and of the key immunological pathways involving distinctive isoforms in the tumor microenvironment, are critical to improve the drug targeting of PKC. We believe that a more inclusive view of the impact of different PKC variants on both cancer and immune cells should guide future efforts, which must consider current immunotherapy strategies. Also, a comprehensive representation of the pathways and partners involving PKC variants may help provide response biomarkers, which can indicate whether or which PKC isoform can be proficiently targeted, potentially in a feasible combination with immune checkpoint blockade. ABSTRACT: The frequent PKC dysregulations observed in many tumors have made these enzymes natural targets for anticancer applications. Nevertheless, this considerable interest in the development of PKC modulators has not led to the expected therapeutic benefits, likely due to the complex biological activities regulated by PKC isoenzymes, often playing ambiguous and protective functions, further driven by the occurrence of mutations. The structure, regulation and functions of PKCs have been extensively covered in other publications. Herein, we focused on PKC alterations mostly associated with complete functional loss. We also addressed the modest yet encouraging results obtained targeting PKC in selected malignancies and the more frequent negative clinical outcomes. The reported observations advocate the need for more selective molecules and a better understanding of the involved pathways. Furthermore, we underlined the most relevant immune mechanisms controlled by PKC isoforms potentially impacting the immune checkpoint inhibitor blockade-mediated immune recovery. We believe that a comprehensive examination of the molecular features of the tumor microenvironment might improve clinical outcomes by tailoring PKC modulation. This approach can be further supported by the identification of potential response biomarkers, which may indicate patients who may benefit from the manipulation of distinctive PKC isoforms.