Why PKC inhibitors fail: Protein Kinase Cs suppress tumours according to new study
As a rule, kinase inhibition is a good way of treating cancer.
For example Gleevec (Imatinib), which targets ABL and KIT kinases, is an effective therapy for chronic myelogenous leukaemia and gastric cancers.
Similarly, newer drug candidates that target EGFR and BRAF kinases are showing promise as treatments for skin and lung cancers.
But while this may be true in general, it does not apply to all kinases with Protein Kinase Cs (PKC) being the notable exception.
Dismal PKC drugs
PKC enzymes have been a target for drugmakers since the early 80s when research identified them as receptors for the known cancer tumour promoter, phorbol ester.
Subsequent research focused on blocking PKC activity in a variety of cancers and other diseases. But despite efforts by firms like Eli Lilly, ISIS Pharmaceuticals and others, little progress has been made.
Now researchers from the University of Manchester, UK and Havard Medical School, US think they know why.
They say PKC inhibition failed as a therapeutic strategy because, rather than promoting tumour development, PKCs actually slow cancer growth.
Fixing mutant genes
The scientists – whose work is published in the journal Cell – used CRISPR gene editing to fix mutant versions of PKC genes in mice.
They found that tumour growth was suppressed in animals in which enzyme function had been restored compared with those in which mutations persisted.
The discovery has significant implications for drug development and clinical research according to lead researcher John Brognard from the Cancer Research UK Manchester Institute.
He told us: “PKC inhibitors have been developed and tested in patients with cancer and the results have been dismal with the inhibitors performing below the standard of care chemotherapy and often exacerbate tumour development.”
“Our results are consistent with the clinical observation as PKC is inactivated in cancers, therefore supplying a drug that inactivates the kinase would be expected to promote tumour development.
Brognard added that: "Instead developing therapies that would activate PKCs may be a more viable option."
Source: Cell
Cancer-Associated Protein Kinase C Mutations Reveal Kinase’s Role as Tumor Suppressor. Antal CE et al. (2015) Cell.
