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

Jolien Van Den Bossche,Jan Baptist Vermorken,Ines De Pauw,Pol Specenier,Filip Lardon,Patrick Pauwels,Andreas Domen,Marc Peeters,Christophe Deben,Sven De Bruycker,Julie Jacobs,An Wouters

doi:10.3390/cancers11121893

Jolien Van Den Bossche, Jan Baptist Vermorken + Show 10 more

Open Access

https://doi.org/10.3390/cancers11121893

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Journal: Cancers	Publication Date: Nov 28, 2019
Citations: 7	License type: CC BY 4.0

Affiliation: University of Antwerp, Antwerp University Hospital

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.

Highlights

Targeting mitosis is a validated approach in cancer research, and agents that affect the mitotic spindle are well-established components of many oncotherapeutic regimes in the clinic
In order to further unravel the difference in radiosensitization in p53 wild type versus p53 knockdown/mutant non-small cell lung cancer (NSCLC) cells, we investigated the cell cycle distribution, induction of apoptotic cell death and cellular senescence after volasertib followed by irradiation
In line with our previous work [21], we showed that volasertib monotherapy induced significantly more senescence in p53 wild type cells compared to their p53 knockdown/mutant counterparts

Summary

Introduction

Targeting mitosis is a validated approach in cancer research, and agents that affect the mitotic spindle are well-established components of many oncotherapeutic regimes in the clinic. Upregulation of Plk has been reported in several tumor types, including NSCLC In these studies, high Plk 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]. Volasertib, at present the lead agent in the category of Plk inhibitors, has been shown to induce mitotic arrest and cell death with a high efficacy in vitro, and to inhibit tumor growth in xenograft models [4,11,12,13]. The highly promising preclinical data obtained in solid tumor types, including NSCLC, could only be confirmed to a lesser extent in patients, with partial response reported in only a limited number of cases [4,11]. The small proportion of patients with meaningful clinical benefit might be masked among a larger proportion of patients who fail to benefit from Plk inhibition since no meaningful biomarkers were taken into account in most early phase clinical trials involving NSCLC [11]

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