Purpose: Glustaminase 1 (GLS1) plays an important role in cellular redox homeostasis and providing substrates for metabolism. We hypothesized that GLS1 inhibition is a radiation sensitizer due to its inhibition of cellular oxidative stress mechanisms. We also hypothesized that RBE would be increased in the setting of GLS1 inhibition because protons can generate greater levels of oxidative stress compared to x-rays. We sought to quantify the effect of IACS-6274, a GLS1 inhibitor, on radiosensitization of both X-rays and protons and on the relative biological effectiveness (RBE) of protons in lung cancer cells.
Methods: Clonogenc survival assays were performed with NCI-H460 cells. Cells were seeded into 6 well plates and irradiated with 6 MV x-rays or 9.9 keV/μm (dose-weighted LET) protons. Cells were treated with a vehicle control, 0.1 or 1 μM IACS-6274, a GLS1 inhibitor. The inhibitor was added 6 hours prior to irradiation and removed after a total incubation time of 24 hours. Data were fit to the linear quadratic model, from which various survival parameters were determined. The RBE was determined for each inhibitor concentration and vehicle control.
Results: We observed that IACS-6274 could radiosensitize NCI-H460 to x-rays and protons. We also observed that the RBE was significantly increased in the presence of IACS-6274 compared to vehicle control (0.1 μM p<.0011; 1 μM p<0.0001).
Conclusion: Our results suggest GLS1 inhibition is an effective strategy for tumor radiosensitization. These findings also demonstrate protons particularly synergize with GLS1 inhibition. This work provides a rationale for further investigation of GLS1 inhibition combined with x-ray and particle radiotherapy. Other inhibitors targeting oxidative stress and metabolism likely warrant investigation, as will the combination of GLS1 and other drugs in this class combined with heavier charged particles such as helium and carbon.
Funding Support, Disclosures, and Conflict of Interest: Drs Sawakuchi and Shaitelman have research funds from Alpha Tau Medical and Artios Pharma.
Protons, RBE, Radiosensitivity
TH- Radiobiology(RBio)/Biology(Bio): RBio- Particle therapy- Protons