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.

Tumor microenvironment signaling and therapeutics in cancer progression

“…PKC is a family of structurally related serine/threonine kinases that functions as the transducer of signals from a variety of molecules ranging from hormones (adrenaline, angiotensin), growth factors (insulin, epidermal growth factor), cytokines (Tumour necrosis factor α (TNF‐α), IL‐1β and IL‐6) and neurotransmitters (i.e., dopamine, endorphins) to regulate cell survival, proliferation, differentiation, apoptosis, adhesion and malignant transformation [ 105 , 110 , 111 ]. The binding of ligands to their receptors can activate phospholipase C, leading to the upregulation of cytosolic concentrations of the activators of PKC signaling, diacylglycerol (DAG) and Ca ++ [ 112 , 113 ]. The activation of PKC can upregulate several molecular pathways, including Akt, signal transducer and activator of transcription 3 (STAT3), nuclear factor‐κB (NF‐κB) and apoptotic pathways, to regulate tumorigenesis and metastasis [ 112 ].…”

Chiral 2‐phenyl‐3‐hydroxypropyl esters as PKC‐alpha modulators: HPLC enantioseparation, NMR absolute configuration assignment, and molecular docking studies

“…The role of PKC family in the modulation of both proliferative and apoptotic signaling clearly makes PKC as an attractive target in cancer, with pharmacological modulators aimed to either dampen or trigger PKC‐mediated signaling given that the different PKC isoforms can act as either oncogenes or oncosuppressors. Mentioning just one recent evidence on a widespread malignant tumor, PKC isoform α, ε, η, ι, ζ upregulation has been reported in non‐small cell lung cancer, where PKC overexpression correlates with worse prognosis in these patients 10 …”

“…Mentioning just one recent evidence on a widespread malignant tumor, PKC isoform α, ε, η, ι, ζ upregulation has been reported in non-small cell lung cancer, where PKC overexpression correlates with worse prognosis in these patients. 10 Further, various PKC isoforms are involved in brain development and memory function, 11,12 and PKC alterations have been documented in diverse brain pathologies, such as epilepsy, stroke, and neurodegenerative diseases, including Alzheimer's disease (AD). 13,14 In particular, PKCα activation mediates the physiological, nonamyloidogenic, α-secretase-mediated processing of the amyloid precursor protein (APP), a central element in AD pathophysiology 15 ; positive effects of PKCα activation on memory have been reported in vivo in an AD model.…”

Antiproliferative activity of a new derivative from the class of N-glycoside of indolo[2,3-a]pyrrolo[3,4-c]carbazoles

“…The manifestation of high antiproliferative activity in such compounds as rebeccamycin and staurosporine determined the search for effective antitumor drugs among their synthetic analogues and low molecular weight derivatives with lower toxic properties. The representatives of this class: midostaurin (Li et al 2022), enzastaurin (Sadeghi et al 2021), lestaurtinib (Kangussu-Marcolino and Singh 2022), becatecarin (Schwandt et al 2012), and edotecarin (Buzun et al 2020) are undergoing clinical trials. The introduction of new antitumor agents from N-glycosides of indolocarbazoles class into clinical practice is also extremely important for overcoming the drug resistance of tumor cells to treatment.…”