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

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).

Figure 1

An overview of lung cancer histology and driver mutations in adenocarcinoma patients.

Figure 2

A schematic representation of PKC subfamily structural domains. Distinct PKC isozymes are categorized into classical, novel, or atypical PKCs based on N-terminal regulatory domain structure and have conserved C1-4 domains. Classical PKC α, β1, β2, γ are activated by DAG and calcium through binding with C1A-C1B and C2 domain, respectively. Novel PKC isoforms δ, ε, η, θ are DAG dependent but calcium independent for their activation, as the C2-like domain cannot bind calcium. Atypical PKC ζ, ι do not respond to calcium or DAG. All PKC isozymes have a pseudosubstrate (PS) domain involved in kinase auto-inhibition. The C-terminal catalytic domain is highly homologous between all the PKC isozymes and consists of an ATP binding C3 domain and a C4 kinase domain.

Figure 3

A scheme defining the biological roles of PKC in NSCLC.

Figure 4

A scheme outlining PKC-mediated drug resistance in EGFR and KRAS mutant NSCLC.