Hypoxic tumors are sensitive to FLASH radiotherapy

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.