Synergistically Overcoming Tumor Radioresistance By Combining High-LET α-Particle Radiotherapy with ATR Inhibition
Abstract
Purpose
To combat radioresistance by combining high linear energy transfer (LET) α-particles from diffusing alpha-emitters radiotherapy (Alpha-DaRT) with an inhibitor of ATR (Ataxia Telangiectasia and Rad3-related) (ATRi), a DNA repair protein that is involved in homologous recombination repair and activation of the G2 cell cycle checkpoint.
Methods
The radioresistant murine pancreatic cancer cell line KPC was inoculated (day 0) into the lower left leg (5×10⁵ cells) or both lower legs (1×10⁵ cells in the lower right leg) of C57BL/6 mice. After 7 and 10 days, respectively, a single Alpha-DaRT source (Ra-224, 75 kBq) or inert source was implanted into the left tumor. ATRi (AZD6738, 75 mg/kg) or vehicle (DMSO) was administered via oral gavage for three consecutive days with a four-day break and then another three consecutive days, with the first dose starting two hours prior to Alpha-DaRT source implantation. Tumor volume was measured three times per week using calipers.
Results
In mice inoculated with a single tumor, combined treatment (Alpha-DaRT+ATRi) significantly delayed tumor growth compared to non-treated and monotherapies (Alpha-DaRT or ATRi) by days 10 and 20, respectively. The combined treatment yielded a significant synergistic effect (p<0.0005) in mice with a single tumor. In mice with two tumors, the irradiated tumor(left) of the combined treatment group presented significant tumor growth delay by day 13 compared to non-treated and monotherapies. For the non-irradiated tumor, Alpha-DaRT monotherapy slightly and non-significantly delayed tumor growth compared to control, while ATRi monotherapy and combined therapy significantly delayed tumor growth compared to control at day 13.
Conclusion
High-LET α-particles are promising against highly radioresistant tumors. The combination of an ATR inhibitor acts synergistically on the local tumor. Several alpha emitters and ATR inhibitors are in clinical trials and their combination is a promising clinical strategy to combat resistance to treatment.