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A Method for Screening and Validation of Resistant Mutations Against Kinase Inhibitors

A Method for Screening and Validation of Resistant Mutations Against Kinase Inhibitors

Published on: December 7, 2014

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

Angelo Aquino¹, Nicoletta Bianchi², Anna Terrazzan^2,3

¹Department of Systems Medicine, University of Rome Tor Vergata, 00133 Rome, Italy.

|August 26, 2023

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.

Insights

Protein kinase C (PKC) dysregulation in cancer presents therapeutic challenges. Tailoring PKC modulation strategies and identifying biomarkers are crucial for improving anticancer treatment outcomes.

Area of Science:

Biochemistry
Oncology
Immunology

Background:

Protein kinase C (PKC) enzymes are frequently dysregulated in tumors, making them targets for cancer therapy.
Despite interest, PKC modulators have yielded limited therapeutic benefits due to complex, often protective, roles of PKC isoenzymes and mutations.
This review focuses on PKC alterations linked to functional loss and clinical outcomes in cancer treatment.

Purpose of the Study:

To review PKC alterations in cancer, focusing on functional loss.
To analyze the clinical outcomes of targeting PKC in malignancies.
To explore PKC's role in immune mechanisms and its impact on immunotherapy.

Main Methods:

Literature review of PKC structure, regulation, function, and alterations in cancer.
Analysis of clinical trial data and reported outcomes for PKC-targeted therapies.
Examination of immunological pathways regulated by PKC isoforms.

Main Results:

PKC dysregulation is common in cancer, but targeting PKC has shown mixed results, with frequent negative clinical outcomes.
PKC alterations associated with functional loss are prevalent.
PKC isoforms significantly influence immune mechanisms, affecting responses to immune checkpoint inhibitors.

Conclusions:

There is a need for more selective PKC-targeting molecules and a deeper understanding of involved pathways.
Tailoring PKC modulation based on tumor microenvironment features and identifying response biomarkers can improve clinical outcomes.
Understanding PKC's immune functions may enhance immunotherapy efficacy.

Read full analysis

Keywords:

PKC PKC inhibitors PKC isoforms PKC mutations cancer therapy immune cells immune checkpoint inhibitor blockade immune checkpoint molecules

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