Targeting protein kinase C subtypes in pancreatic cancer

Abstract

In preclinical studies, protein kinase C (PKC) enzymes have been implicated in regulating many aspects of pancreatic cancer development and progression. However, clinical Phase I or Phase II trials with compounds targeting classical PKC isoforms were not successful. Recent studies implicate that mainly atypical and novel PKC enzymes regulate oncogenic signaling pathways in pancreatic cancer. Members of these two subgroups converge signaling induced by mutant Kras, growth factors and inflammatory cytokines. Different approaches for the development of inhibitors for atypical PKC and novel PKC have been described; and new compounds include allosteric inhibitors and inhibitors that block ATP binding.

Keywords:

• inhibitor
• pancreatic cancer
• protein kinase C
• therapy

Financial & competing interests disclosure

P Storz was supported by R01-CA140182 from the NIH. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Key issues

• Different protein kinase C (PKC) isoforms have been implicated in pancreatic cancer.

• Clinical trials targeting classical PKC isoforms were not successful.

• Preclinical data indicate important functions for atypical PKC (aPKC) and novel PKC (nPKC) in pancreatic cancer.

• aPKC and nPKC drive activation of NF-κB and STAT3.

• Inhibitors for aPKC and nPKC have been tested in preclinical studies.

• Inhibitors for aPKC and nPKC now need testing in clinical trials.

• Combination therapy with currently used chemotherapeutic drugs may be effective.

Notes