Abstract
Tumor hypoxia is a major cause of resistance to cancer treatments and especially to radiotherapy. To address this specifically, we investigated whether ultra-high dose rate FLASH radiotherapy could overcome this resistance. Tumor cells from various origins were engrafted subcutaneously in mice to provide a reliable and rigorous way to modulate oxygen supply by vascular clamping or carbogen breathing. Tumors were irradiated using a single 20 Gy fraction at both conventional (CONV) and FLASH dose-rates using the Oriatron/eRT6 (PMB-Alcen, FR). Interestingly, and unlike radiotherapy at conventional dose rate, FLASH maintains its anti-tumor efficacy under extreme hypoxia. These findings demonstrate that in addition to normal tissue sparing, FLASH overcomes hypoxia-mediated tumor resistance. Follow-up molecular analysis using RNA-seq profiling uncovered specific metabolic shifts that discriminated FLASH from conventional dose rate irradiation, data that provides specific insights into the mechanism of action and identifies new targets for interventions.
Competing Interest Statement
The authors have declared no competing interest.
Footnotes
Funding information: SNFS grant MAGIC- FNS CRS II5_186369. RL and VG (partially) were supported by MAGIC- FNS CRS II5_186369. AA and VG (partially) were supported by NIH grant P01CA244091-01. PMG was supported by FNS N°31003A_156892.
Conflict of Interest Declaration: Authors declare no conflict of interest.
Institutional Animal Care and Use Committee (IACUC) or Other Approval Declaration: The study was approved by the Animal Ethics Council of the Canton of Vaud, Switzerland (number: VD 3241 – VD 3603 – VD 3670).
