Towards Prognostic Profiling of Non-Small Cell Lung Cancer: New Perspectives on the Relevance of Polo-Like Kinase 1 Expression, the TP53 Mutation Status and Hypoxia

Abstract

Background: Currently, prognosis of non-small cell lung cancer (NSCLC) patients is based on clinicopathological factors, including TNM stage. However, there are considerable differences in patient outcome within a similar staging group, even when patients received identical treatments. In order to improve prognostic predictions and to guide treatment options, additional parameters influencing outcome are required. Polo-like kinase 1 (Plk1), a master regulator of mitotic cell division and the DNA damage response, is considered as a new potential biomarker in this research area. While several studies reported Plk1 overexpression in a broad range of human malignancies, inconsistent results were published regarding the clinical significance hereof. A prognostic panel, consisting of Plk1 and additional biomarkers that are related to the Plk1 pathway, might further improve prediction of patient prognosis.Methods: In this study, we evaluated for the first time the prognostic value of Plk1 mRNA and protein expression in combination with the TP53 mutation status (next generation sequencing), induction of apoptotic cell death (immunohistochemistry for cleaved caspase 3) and hypoxia (immunohistochemistry for carbonic anhydrase IX (CA IX)) in 98 NSCLC adenocarcinoma patients.Results: Both Plk1 mRNA and protein expression and CA IX protein levels were upregulated in the majority of tumor samples. Plk1 mRNA and protein expression levels were higher in TP53 mutant samples, suggesting that Plk1 overexpression is, at least partially, the result of loss of functional p53 (<0.05). Interestingly, the outcome of patients with both Plk1 mRNA and CA IX protein overexpression, who also harbored a TP53 mutation, was much worse than that of patients with aberrant expression of only one of the three markers (p=0.001).Conclusion: The combined evaluation of Plk1 mRNA expression, CA IX protein expression and TP53 mutations shows promise as a prognostic panel in NSCLC patients. Moreover, these results pave the way for new combination strategies with Plk1 inhibitors.

Identification of the key genes and characterizations of Tumor Immune Microenvironment in Lung Adenocarcinoma (LUAD) and Lung Squamous Cell Carcinoma (LUSC)

“…PLK1, Polo Like Kinase 1, encodes a Ser/Thr protein kinase of the CDC5/Polo subfamily that is essential in mitotic progression [44]. Jolien et al demonstrated that the level of PLK1 was increased in LUAD, and the combined evaluation of PLK1, carbonic anhydrase IX, and TP53 could predict prognosis of LUAD patients [45]. Noboru et al showed that the expression of karyopherin beta 1 could be decreased by inhibiting PLK1, and such a decrease could inhibit cell proliferation via apoptosis in LUAD cells [46].…”

Radiosensitization of Non-Small Cell Lung Cancer Cells by the Plk1 Inhibitor Volasertib Is Dependent on the p53 Status

“…Upregulation of Plk1 has been reported in several tumor types, including NSCLC. In these studies, high Plk1 expression levels correlated with poor patient prognosis, corroborating its importance in tumor progression and its potential as a therapeutic target [7][8][9][10][11]. So far, several small molecule inhibitors of Plk1 have been developed and are currently being evaluated in clinical trials.…”

“…Elevated levels of Plk1, a crucial kinase during mitotic cell division, have been described in multiple cancer types, including NSCLC, with high expression levels being associated with poor survival [7,8,11]. Notwithstanding encouraging preclinical effectiveness of Plk1 inhibition, clinical trials with volasertib have shown only mild antitumor activity as a single agent [9,11]. As new combination strategies are key to improving clinical outcome of NSCLC patients, we aimed to study the in vitro effects of volasertib in combination with radiotherapy.…”

The role of the CDCA gene family in ovarian cancer

“…According to our results, attention should be paid to some pathways, which include: R-HAS-2500257: resolution of sister chromatid cohesion; GO: 0051301: cell division; CORUM: 1118: Chromosomal passenger complex (CPC, including CDCA8, INCENP, AURKB, and BIRC5); CORUM: 127: NDC80 kinetochore complex; M129: PID PLK1 pathway; GO: 0007080: mitotic metaphase plate congression. As a primary regulator of mitotic cell division and the DNA damage response, Polo-like kinase 1 (Plk1) is recognized as a new feasible biomarker in this area (46). PLK1 pathway has been revealed to exert certain function in patients with advanced solid malignancies (47), human hepatocellular carcinoma (HCC) (48,49), and glioma (50).…”