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Updated: Jun 28, 2026

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 kinases and multidrug resistance.

M G Rumsby¹, L Drew, J R Warr

¹Department of Biology, University of York, York, YO1 5YW, England., mgr1@york.ac.uk.

|November 13, 2008

Summary

Protein kinase C (PKC) and protein kinase A (PKA) roles in cancer multidrug resistance (MDR) were examined. While PKA influences P-glycoprotein gene expression, PKC

Area of Science:

Biochemistry
Molecular Biology
Cancer Research

Background:

Multidrug resistance (MDR) is a major challenge in cancer chemotherapy.
Protein kinases, including protein kinase C (PKC) and protein kinase A (PKA), are implicated in MDR.
P-glycoprotein (P-gp) is a key efflux pump contributing to MDR.

Purpose of the Study:

To review the role of PKC and PKA in the MDR phenotype of cancer cell lines.
To summarize evidence linking P-gp phosphorylation by these kinases to MDR.
To discuss the relationship between kinase activity/expression and MDR.

Main Methods:

Literature review of studies investigating protein kinase involvement in MDR.
Analysis of evidence for P-gp phosphorylation by PKC and PKA.

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Examination of co-immunoprecipitation and revertant experiments.

Discussion of drug inhibitor and phorbol ester studies.

Main Results:

PKA influences P-gp expression at the gene level, with clarifying mechanisms.
PKC, particularly the alpha subspecies, is often overexpressed in MDR cell lines, but this is drug- and cell line-dependent.
Co-immunoprecipitation suggests P-gp may be a specific PKC receptor and substrate.
Direct correlation between PKC activity and MDR is not universally established, and some results are conflicting.
Evidence for PKC regulating Pgp-independent drug resistance mechanisms is growing.

Conclusions:

PKA has a documented role in regulating P-gp gene expression in MDR.
The direct involvement of PKC in regulating MDR is not firmly established, despite extensive research.
PKC may contribute to drug resistance through P-gp-independent pathways.