期刊
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
卷 22, 期 11, 页码 -出版社
MDPI
DOI: 10.3390/ijms22115527
关键词
non-small cell lung cancer (NSCLC); targeted therapy; chemotherapy; protein kinase C (PKC); drug resistance; epidermal growth factor receptor (EGFR); tyrosine kinase inhibitors (TKI); enzastaurin
资金
- Department of Veterans Affairs [I01 BX004621]
Driver-directed therapeutics have significantly improved cancer treatment efficacy and quality of life, but resistance acquisition remains a major challenge in targeted therapy for NSCLC. PKC isoforms have been implicated as mediators of drug resistance in NSCLC, with upregulation correlating with worse prognosis. Predictive biomarkers for PKC activity are needed for better results in clinical trials, and tandem inhibition of PKC and molecular drivers may offer a potential therapeutic strategy to prevent resistance emergence.
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 alpha, epsilon, eta, iota, zeta 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.
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