Einfluss des dualen Targetings des PI3K/mTOR- und MAP-Kinase-Signalweges auf die Strahlenempfindlichkeit von nicht-kleinzelligen Lungenkarzinomzellen bei Bestrahlung mit Photonen und Kohlenstoffionen
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Philipps-Universität Marburg
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Abstract
The MAPK and PI3K/mTOR signaling pathways are two of the most important signaling pathways in tumors and are often involved in the development of resistance to therapies. Ionizing radiation activates these signaling pathways. Consecutively induced DNA repair mechanisms result in long-term radiation and thus therapy resistance of tumors. In this study, six different NSCLC cell lines with different mutation profiles regarding p53, EGFR and K-Ras were investigated (A549, H460, H1975, H520, H661 and H1299). The cells were treated with the MAPK inhibitor PD98059 (50 μM), the PI3K/mTOR inhibitor NVP-BEZ235 (50 nM) or a combination of the two inhibitors and then irradiated with photons or with carbon ions. The survival fraction of the cells after treatment and irradiation was assessed
using a colony formation assay.
The experiments provided the following results:
1. The use of PD98059 (50 μM) and NVP-BEZ235 (50 nM) alone or double targeting by combining both inhibitors had no effect on the colony-forming ability of the examined NSCLC cell lines without consecutive irradiation.
2. All NSCLC cell lines investigated are significantly more sensitive to carbon ions than to photons at physical dose equivalence. In the cell lines H1299, H1975, H661 and A549 the relative biological effectiveness is three.
3. The use of PD98059 (50 μM) sensitizes the cell lines A549, H1299 and H1975 to
photons at a dose of 2 Gy. At higher doses there is no additional benefit from the
inhibitor application compared to the effect of radiation alone regarding the colony-forming ability.
4. NVP-BEZ235 (50 nM) can enhance the radiation effect by photons in all examined NSCLC cell lines. This radiosensitization occurs regardless of the dose of radiation.
5. The radiosensitizing effect of NVP-BEZ235 (50 nM) can be increased by double targeting. The cell lines A549 and H1299 benefit from double targeting from a dose of 6 Gy on. Cells of the H1975 cell line already show a benefit from double targeting with doses from 2 Gy and higher. In contrast to these cell lines a desensitisation against the radiation in comparison to the isolated treatment with NVP-BEZ235 can be observed in the H520 cell line.
6. The treatment with PD98059 (50 μM) does not sensitize the examined cell lines against the effects of carbon ion irradiation.
7. The treatment with NVP-BEZ235 (50 nM) leads to radiosensitization of the examined cell lines against carbon ion irradiation.
8. Double targeting of the MAPK and PI3K/mTOR signaling pathway in comparison to isolated treatment with NVP-BEZ235 (50 nM) show no benefit in clonogenic survival after carbon ion irradiation with a dose of 2 Gy.
9. Both double targeting and the isolated use of NVP-BEZ235 (50 nM) on the examined cells mainly show a radiosensitization against photon irradiation. The radiosensitizing effect against carbon ion irradiation is observable but not as pronounced.
When irradiated with photons, lethal double-strand breaks are induced. These cannot be repaired by the non-homologous end joining repair mechanism, as this is inhibited by NVP-BEZ235. This results in increased radiosensitivity. Double targeting also prevents the reactivation of the MAPK signaling pathway due to feedback mechanisms between the signaling pathways. However, the success of double targeting is highly dependent on factors such as inhibitor selection, time between inhibitor treatment and irradiation, irradiation dose and in particular the tumor entity of the cells and their mutation profile. Further studies are required
to identify those tumor cells that would benefit from double targeting. In the long term, this could lead to the development of a therapy concept for NSCLC with targeted dual inhibition. This work shows that the use of NVP-BEZ235 also sensitizes the cells to irradiation with carbon ions. Double targeting did not result in an increase in radiation sensitization to carbon ions. One possible explanation could be the lack of activation of the MAPK and PI3K/mTOR signaling pathways after irradiation with carbon ions. This should be investigated in further experiments. Since the repair of damage caused by carbon ions is increasingly taking place via alternative repair mechanisms, such as alternative end-joining or single-strand annealing, inhibition of these repair mechanisms with consecutive irradiation with carbon ions would be another interesting research approach.
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Created: 2025Issued: 2025-05-15Updated: 2025-05-15
Faculty
Medizin
Publisher
Philipps-Universität Marburg
Language
ger
Data types
DoctoralThesis
DFG-subjects
PhotonenKohlenstoffionenDoppeltargetingNSCLCStrahlenbiologieMAP-Kinase-SignalwegPI3K/mTOR- Signalweg
DDC-Numbers
610
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Ziesenitz, Vanessa Sandamali (0009-0001-6512-9011): Einfluss des dualen Targetings des PI3K/mTOR- und MAP-Kinase-Signalweges auf die Strahlenempfindlichkeit von nicht-kleinzelligen Lungenkarzinomzellen bei Bestrahlung mit Photonen und Kohlenstoffionen. : Philipps-Universität Marburg 2025-05-15. DOI: https://doi.org/10.17192/z2025.0205.
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This item has been published with the following license: In Copyright