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Volume 12
Issue 6
10.3390/genes12060925
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Article

Kinase Inhibitors of DNA-PK, ATM and ATR in Combination with Ionizing Radiation Can Increase Tumor Cell Death in HNSCC Cells While Sparing Normal Tissue Cells

by
Eva-Maria Faulhaber
1,2,†,
Tina Jost
1,2,†,
Julia Symank
1,2,
Julian Scheper
1,2,
Felix Bürkel
1,2,
Rainer Fietkau
1,2,
Markus Hecht
1,2,‡ and
Luitpold V. Distel
1,2,*,‡
1
Department of Radiation Oncology, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054 Erlangen, Germany
2
Comprehensive Cancer Center Erlangen-EMN (CCC ER-EMN), 91054 Erlangen, Germany
*
Author to whom correspondence should be addressed.
†
Eva-Maria Faulhaber and Tina Jost contributed equally to this work and are joint first authors.
‡
Markus Hecht and Luitpold V. Distel contributed equally to this work and are joint senior authors.
Genes 2021, 12(6), 925; https://doi.org/10.3390/genes12060925
Submission received: 2 June 2021 / Revised: 13 June 2021 / Accepted: 15 June 2021 / Published: 17 June 2021
(This article belongs to the Special Issue Mechanisms of DNA Damage, Repair and Mutagenesis)
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Abstract

(1) Kinase inhibitors (KI) targeting components of the DNA damage repair pathway are a promising new type of drug. Combining them with ionizing radiation therapy (IR), which is commonly used for treatment of head and neck tumors, could improve tumor control, but could also increase negative side effects on surrounding normal tissue. (2) The effect of KI of the DDR (ATMi: AZD0156; ATRi: VE-822, dual DNA-PKi/mTORi: CC-115) in combination with IR on HPV-positive and HPV-negative HNSCC and healthy skin cells was analyzed. Cell death and cell cycle arrest were determined using flow cytometry. Additionally, clonogenic survival and migration were analyzed. (3) Studied HNSCC cell lines reacted differently to DDRi. An increase in cell death for all of the malignant cells could be observed when combining IR and KI. Healthy fibroblasts were not affected by simultaneous treatment. Migration was partially impaired. Influence on the cell cycle varied between the cell lines and inhibitors; (4) In conclusion, a combination of DDRi with IR could be feasible for patients with HNSCC. Side effects on healthy cells are expected to be limited to normal radiation-induced response. Formation of metastases could be decreased because cell migration is impaired partially. The treatment outcome for HPV-negative tumors tends to be improved by combined treatment.
Keywords: kinase inhibitors; radiotherapy; targeted therapy; DDR; radiosensitivity; ATM; ATR; DNA-PK kinase inhibitors; radiotherapy; targeted therapy; DDR; radiosensitivity; ATM; ATR; DNA-PK
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MDPI and ACS Style

Faulhaber, E.-M.; Jost, T.; Symank, J.; Scheper, J.; Bürkel, F.; Fietkau, R.; Hecht, M.; Distel, L.V. Kinase Inhibitors of DNA-PK, ATM and ATR in Combination with Ionizing Radiation Can Increase Tumor Cell Death in HNSCC Cells While Sparing Normal Tissue Cells. Genes 2021, 12, 925. https://doi.org/10.3390/genes12060925

AMA Style

Faulhaber E-M, Jost T, Symank J, Scheper J, Bürkel F, Fietkau R, Hecht M, Distel LV. Kinase Inhibitors of DNA-PK, ATM and ATR in Combination with Ionizing Radiation Can Increase Tumor Cell Death in HNSCC Cells While Sparing Normal Tissue Cells. Genes. 2021; 12(6):925. https://doi.org/10.3390/genes12060925

Chicago/Turabian Style

Faulhaber, Eva-Maria, Tina Jost, Julia Symank, Julian Scheper, Felix Bürkel, Rainer Fietkau, Markus Hecht, and Luitpold V. Distel. 2021. "Kinase Inhibitors of DNA-PK, ATM and ATR in Combination with Ionizing Radiation Can Increase Tumor Cell Death in HNSCC Cells While Sparing Normal Tissue Cells" Genes 12, no. 6: 925. https://doi.org/10.3390/genes12060925

APA Style

Faulhaber, E.-M., Jost, T., Symank, J., Scheper, J., Bürkel, F., Fietkau, R., Hecht, M., & Distel, L. V. (2021). Kinase Inhibitors of DNA-PK, ATM and ATR in Combination with Ionizing Radiation Can Increase Tumor Cell Death in HNSCC Cells While Sparing Normal Tissue Cells. Genes, 12(6), 925. https://doi.org/10.3390/genes12060925

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