Protein Kinase C as a Therapeutic Target in Non-Small Cell Lung Cancer

Int J Mol Sci. 2021 May 24;22(11):5527. doi: 10.3390/ijms22115527.

Abstract

Driver-directed therapeutics have revolutionized cancer treatment, presenting similar or better efficacy compared to traditional chemotherapy and substantially improving quality of life. Despite significant advances, targeted therapy is greatly limited by resistance acquisition, which emerges in nearly all patients receiving treatment. As a result, identifying the molecular modulators of resistance is of great interest. Recent work has implicated protein kinase C (PKC) isozymes as mediators of drug resistance in non-small cell lung cancer (NSCLC). Importantly, previous findings on PKC have implicated this family of enzymes in both tumor-promotive and tumor-suppressive biology in various tissues. Here, we review the biological role of PKC isozymes in NSCLC through extensive analysis of cell-line-based studies to better understand the rationale for PKC inhibition. PKC isoforms α, ε, η, ι, ζ upregulation has been reported in lung cancer, and overexpression correlates with worse prognosis in NSCLC patients. Most importantly, PKC isozymes have been established as mediators of resistance to tyrosine kinase inhibitors in NSCLC. Unfortunately, however, PKC-directed therapeutics have yielded unsatisfactory results, likely due to a lack of specific evaluation for PKC. To achieve satisfactory results in clinical trials, predictive biomarkers of PKC activity must be established and screened for prior to patient enrollment. Furthermore, tandem inhibition of PKC and molecular drivers may be a potential therapeutic strategy to prevent the emergence of resistance in NSCLC.

Keywords: chemotherapy; drug resistance; enzastaurin; epidermal growth factor receptor (EGFR); non-small cell lung cancer (NSCLC); protein kinase C (PKC); targeted therapy; tyrosine kinase inhibitors (TKI).

Publication types

  • Review

MeSH terms

  • Carcinoma, Non-Small-Cell Lung / drug therapy*
  • Carcinoma, Non-Small-Cell Lung / genetics
  • Carcinoma, Non-Small-Cell Lung / metabolism*
  • Drug Resistance, Neoplasm*
  • ErbB Receptors / genetics
  • ErbB Receptors / metabolism
  • Humans
  • Indoles / pharmacology*
  • Lung Neoplasms / drug therapy*
  • Prognosis
  • Protein Isoforms / genetics
  • Protein Isoforms / metabolism
  • Protein Kinase C / antagonists & inhibitors
  • Protein Kinase C / metabolism*
  • Protein Kinase Inhibitors / pharmacology
  • Proto-Oncogene Proteins p21(ras) / genetics
  • Proto-Oncogene Proteins p21(ras) / metabolism

Substances

  • Indoles
  • KRAS protein, human
  • Protein Isoforms
  • Protein Kinase Inhibitors
  • EGFR protein, human
  • ErbB Receptors
  • Protein Kinase C
  • Proto-Oncogene Proteins p21(ras)
  • enzastaurin