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

Abstract

Polo-like kinase 1 (Plk1), a master regulator of mitotic cell division, is highly expressed in non-small cell lung cancer (NSCLC) making it an interesting drug target. We examined the in vitro therapeutic effects of volasertib, a Plk1 inhibitor, in combination with irradiation in a panel of NSCLC cell lines with different p53 backgrounds. Pretreatment with volasertib efficiently sensitized p53 wild type cells to irradiation. Flow cytometric analysis revealed that significantly more cells were arrested in the G2/M phase of the cell cycle after the combination therapy compared to either treatment alone (p < 0.005). No significant synergistic induction of apoptotic cell death was observed, but, importantly, significantly more senescent cells were detected when cells were pretreated with volasertib before irradiation compared to both monotherapies alone (p < 0.001), especially in cells with functional p53. Consequently, while most cells with functional p53 showed permanent growth arrest, more p53 knockdown/mutant cells could re-enter the cell cycle, resulting in colony formation and cell survival. Our findings assign functional p53 as a determining factor for the observed radiosensitizing effect of volasertib in combination with radiotherapy for the treatment of NSCLC.

Investigating Molecular Determinants of Cancer Cell Resistance to Ionizing Radiation Through an Integrative Bioinformatics Approach

“…The protein encoded by the radiogene PLK1 (Polo-like kinase 1) is involved in cell cycle resumption following DNA damage-induced checkpoint arrest (Hyun et al, 2014 ; Bruinsma et al, 2017 ). It has been demonstrated that inhibition of PLK1 renders glioblastoma and non-small cell lung cancer cells sensitive to IR (Pezuk et al, 2013 ; Van den Bossche et al, 2019 ). Of particular note, pharmacological inhibitors of the BER enzyme PARP1 [poly(ADP-ribose) polymerase 1], such as niraparib, olaparib, and rucaparib, are widely used for targeted cancer therapy (Sulai and Tan, 2018 ; Patel et al, 2020 ).…”

Targeting the Hippo pathway to prevent radioresistance brain metastases from the lung (Review)

“…The TGF-β1 inhibitor, SB431542, also induces radiopotentiation in NSCLC cell lines depending on the p53 status of the cells ( 101 ). Inhibition of P1K1 in p53 wild-type NSCLC cells induced radiosensitivity, but this effect was not found in mutated p53 cells ( 102 ). In the second category, the effects of various combinations of DNA damage response inhibitors on NSCLC cell lines have been investigated through the profiling of biomarkers and different genetic alterations ( 103 ).…”

Drug Resistance and Novel Therapies in Cancers in 2019

“…The 26 original research articles covered 13 different cancer types including melanoma [ 1 , 2 , 3 , 4 ], breast cancer [ 5 , 6 , 7 , 8 ], colorectal cancer (CRC) [ 9 , 10 , 11 ], hepatocellular carcinoma [ 12 , 13 , 14 ], glioblastoma [ 15 , 16 ], non-small cell lung cancer (NSCLC) [ 17 , 18 ], prostate cancer [ 19 ], ovarian cancer [ 20 ], pleural mesothelioma [ 21 ], cervical cancer [ 22 ], Leukemia [ 23 ], adenoid cystic carcinoma [ 24 ], and vulvar cancer [ 25 ]. While these studies looked at a broad range of cancer therapies including cytotoxic chemotherapy [ 7 , 8 , 11 , 16 , 20 ], electrochemotherapy [ 25 ], radio therapy [ 2 , 4 , 18 ], proton beam therapy [ 24 ], and oncolytic virus therapy [ 6 ], the most studied are targeted therapies with various means. The cellular process being targeted include glucose metabolism [ 19 ], cell signaling [ 5 ], endoplasmic reticulum (ER) stress [ 21 ], autophagy [ 12 ], angiogenesis [ 10 ], DNA repair [ 4 , 6 ], apoptosis [ 11 ], and microRNA [ 10 , 26 ].…”

“…The cellular process being targeted include glucose metabolism [ 19 ], cell signaling [ 5 ], endoplasmic reticulum (ER) stress [ 21 ], autophagy [ 12 ], angiogenesis [ 10 ], DNA repair [ 4 , 6 ], apoptosis [ 11 ], and microRNA [ 10 , 26 ]. The molecules being targeted include HER2 [ 5 ], VEGF [ 10 ], p53 [ 4 , 13 , 18 ], CDK [ 14 ], BCR-ABL1 and PAK1/2 [ 23 ], PARP1/HMGB1 [ 12 ], mir-221 [ 26 ], miR-31-5p [ 10 ], TIMP-1 [ 17 ], Fox3a [ 8 ], and FOXC1 [ 10 ].…”