KEY POINTS
- Investigators studied seven 3D uveal melanoma spheroid models—92.1, Mel202, Mel270, MP41, MP46, OMM1 and OMM2.3—and combined X-rays or proton beam therapy with inhibitors targeting three major DNA double-strand-break response kinases: ATM, ATR and DNA-PK.
- Baseline radiosensitivity varied substantially. After 2 Gy of X-rays, growth of the 92.1 model fell by approximately 60%, whereas MP41 and OMM2.3 showed only around 10–20% reduction, providing a useful range of intrinsically sensitive and resistant models.
- With X-rays, DNA-PK inhibition produced the largest radiosensitization, with dose-enhancement ratios of 2.5–10.0, followed by ATM inhibition at 1.6–8.0 and ATR inhibition at 1.3–5.6. The magnitude depended heavily on the intrinsic radiosensitivity of each cell line.
- The effect persisted with protons. Across proton-treated spheroids, DNA-PK inhibition produced dose-enhancement ratios of approximately 1.7–5.6 and ATM inhibition 1.9–5.6, again making these the strongest of the tested repair targets.
- Mechanistic experiments showed that the inhibitors prevented normal resolution of radiation-induced DNA double-strand breaks. After proton therapy, DNA-PK inhibition almost completely prevented resolution of γH2AX and 53BP1 signaling through 24 hours, while ATM and ATR inhibition also prolonged damage signaling into the 24–48-hour period.
- X-ray combination treatment also increased micronuclei and other chromosomal abnormalities. ATM and DNA-PK inhibition prolonged G2/M arrest at 24 hours, consistent with persistent unrepaired damage rather than simply nonspecific suppression of cell growth.
- Some enhancement ratios were actually lower with protons than with X-rays, partly because proton irradiation alone already produced greater growth suppression in several models. The experimental proton beam also differed geometrically and had a moderately higher reported linear energy transfer, complicating direct modality comparisons.
CLINICAL TAKEAWAY
DNA-repair inhibition offers a biologically plausible route to increasing uveal-melanoma radiosensitivity and, in principle, could eventually permit better control or lower ocular dose. But these experiments stop at 3D tumor spheroids: there is no evidence yet that systemic or local ATM/DNA-PK inhibition can be delivered safely enough to improve the therapeutic ratio in an eye, where protection of retina, optic nerve and other normal tissues is the entire point.