Impact of p53 Status on Radiosensitization of Tumor Cells by MET Inhibition-Associated Checkpoint Abrogation

Mikami, K.; Medova, Michaela; Nisa Hernandez, Lluis; Francica, Paola; Glück, Astrid Andreina; Tschan, Mario; Blaukat, A.; Bladt, F.; Aebersold, Daniel; Zimmer, Yitzhak (2015). Impact of p53 Status on Radiosensitization of Tumor Cells by MET Inhibition-Associated Checkpoint Abrogation. Molecular cancer research, 13(12), pp. 1544-1553. American Association for Cancer Research AACR 10.1158/1541-7786.MCR-15-0022

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Signaling via the MET receptor tyrosine kinase has been implicated in crosstalk with cellular responses to DNA damage. Our group previously demonstrated that MET inhibition in tumor cells with deregulated MET activity results in radiosensitization via downregulation of the ATR-CHK1-CDC25 pathway, a major signaling cascade responsible for intra-S and G2/M cell cycle arrest following DNA damage. Here we aimed at studying the potential therapeutic application of ionizing radiation in combination with a MET inhibitor, EMD-1214063, in p53-deficient cancer cells that harbor impaired G1/S checkpoint regulation upon DNA damage. We hypothesized that upon MET inhibition, p53-deficient cells would bypass both G1/S and G2/M checkpoints, promoting premature mitotic entry with substantial DNA lesions and cell death in a greater extent than p53-proficient cells. Our data suggest that p53-deficient cells are more susceptible to EMD-1214063 and combined treatment with irradiation than wildtype p53 lines as inferred from elevated γH2AX expression and increased cytotoxicity. Furthermore, cell cycle distribution profiling indicates constantly lower G1 and higher G2/M population as well as higher expression of a mitotic marker p-histone H3 following the dual treatment in p53 knockdown isogenic variant, compared to the parental counterpart.

IMPLICATIONS

The concept of MET inhibition-mediated radiosensitization enhanced by p53 deficiency is of high clinical relevance, since p53 is frequently mutated in numerous types of human cancer. The current data point for a therapeutic advantage for an approach combining MET targeting along with DNA damaging agents for MET positive/p53 negative tumors.

Item Type:	Journal Article (Original Article)
Division/Institute:	04 Faculty of Medicine > Service Sector > Institute of Pathology > Tumour Pathology 04 Faculty of Medicine > Department of Haematology, Oncology, Infectious Diseases, Laboratory Medicine and Hospital Pharmacy (DOLS) > Clinic of Radiation Oncology 04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > DBMR Forschung Mu35 > Forschungsgruppe Radio-Onkologie 04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > DBMR Forschung Mu35 > Forschungsgruppe Radio-Onkologie 04 Faculty of Medicine > Service Sector > Institute of Pathology
Graduate School:	Graduate School for Cellular and Biomedical Sciences (GCB)
UniBE Contributor:	Mikami, Kei, Medova, Michaela, Nisa Hernandez, Lluis, Francica, Paola, Glück, Astrid Andreina, Tschan, Mario Paul, Aebersold, Daniel Matthias, Zimmer, Yitzhak
Subjects:	600 Technology > 610 Medicine & health 500 Science > 570 Life sciences; biology
ISSN:	1541-7786
Publisher:	American Association for Cancer Research AACR
Language:	English
Submitter:	Doris Haefelin
Date Deposited:	07 Dec 2015 11:50
Last Modified:	02 Mar 2023 23:26
Publisher DOI:	10.1158/1541-7786.MCR-15-0022
PubMed ID:	26358474
URI:	https://boris.unibe.ch/id/eprint/73730