TY - JOUR T1 - Hypoxic tumors are sensitive to FLASH radiotherapy JF - bioRxiv DO - 10.1101/2022.11.27.518083 SP - 2022.11.27.518083 AU - Ron J Leavitt AU - Aymeric Almeida AU - Veljko Grilj AU - Pierre Montay-Gruel AU - CĂ©line Godfroid AU - Benoit Petit AU - Claude Bailat AU - Charles L Limoli AU - Marie-Catherine Vozenin Y1 - 2022/01/01 UR - http://biorxiv.org/content/early/2022/11/28/2022.11.27.518083.abstract N2 - 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 StatementThe authors have declared no competing interest. ER -