Radiosensitization of NSCLC cells by EGFR inhibition is the result of an enhanced p53-dependent G1 arrest

Radiotherapy and Oncology : Journal of the European Society for Therapeutic Radiology and Oncology
Malte KriegsEkkehard Dikomey

Abstract

How EGF receptor (EGFR) inhibition induces cellular radiosensitization and with that increase in tumor control is still a matter of discussion. Since EGFR predominantly regulates cell cycle and proliferation, we studied whether a G1-arrest caused by EGFR inhibition may contribute to these effects. We analyzed human non-small cell lung cancer (NSCLC) cell lines either wild type (wt) or mutated in p53 (A549, H460, vs. H1299, H3122) and HCT116 cells (p21 wt and negative). EGFR was inhibited by BIBX1382BS, erlotinib or cetuximab; p21 was knocked down by siRNA. Functional endpoints analyzed were cell signaling, proliferation, G1-arrest, cell survival as well as tumor control using an A549 tumor model. When combined with IR, EGFR inhibition enhances the radiation-induced permanent G1 arrest, though solely in cells with intact p53/p21 signaling. This increase in G1-arrest was always associated with enhanced cellular radiosensitivity. Strikingly, this effect was abrogated when cells were re-stimulated, suggesting the initiation of dormancy. In line with this, only a small non-significant increase in tumor control was observed for A549 tumors treated with fractionated RT and EGFR inhibition. For NSCLC cells increase in radiosensitivity ...Continue Reading

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Citations

Oct 16, 2015·BMC Cancer·James A BonnerEddy S Yang
Oct 1, 2015·Radiotherapy and Oncology : Journal of the European Society for Therapeutic Radiology and Oncology·Laura MyllynenMalte Kriegs
Aug 4, 2015·Evidence-based Complementary and Alternative Medicine : ECAM·Woori BaeJoohee Jung
Jun 2, 2016·BMC Veterinary Research·Fernanda B MantovaniAnthony J Mutsaers
Jul 1, 2015·Nature Reviews. Clinical Oncology·Dörthe Schaue, William H McBride
Jul 31, 2019·International Journal of Cancer. Journal International Du Cancer·Kristin GurtnerMechthild Krause
Oct 6, 2017·Oncotarget·Helen H W Chen, Macus Tien Kuo
Mar 26, 2016·Oncotarget·Nikolaus MöckelmannMalte Kriegs
Sep 21, 2019·Scientific Reports·Malte KriegsAdrian Münscher
Sep 13, 2020·Molecular and Cellular Biochemistry·Ziyao ZhuangYunfei Zheng

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