A perspective on tumor radiation resistance following high-LET radiation treatment

Abstract

High-linear energy transfer (LET) radiation is a promising alternative to conventional low-LET radiation for therapeutic gain against cancer owing to its ability to induce complex and clustered DNA lesions. However, the development of radiation resistance poses a significant barrier. The potential molecular mechanisms that could confer resistance development are translesion synthesis (TLS), replication gap suppression (RGS) mechanisms, autophagy, epithelial-mesenchymal transition (EMT) activation, release of exosomes, and epigenetic changes. This article will discuss various types of complex clustered DNA damage, their repair mechanisms, mutagenic potential, and the development of radiation resistance strategies. Furthermore, it highlights the importance of careful consideration and patient selection when employing high-LET radiotherapy in clinical settings.

Keywords: Clustered DNA lesions; Linear energy transfer (LET); Photon therapy; Relative biological effectiveness (RBE); Translesion synthesis (TLS).

Fig. 1

The biological effects and possible radiation resistance mechanisms against high-LET radiotherapy (RT). Cellular responses to both low and high-LET radiation offer valuable insights into the biological ramifications. Low-LET radiation (X-rays, γ-rays) causes sparsely distributed DNA damage (DSBs, SSBs, and oxidized bases) (1) in the genome, while high-LET radiation (α-particles, carbon ions, and protons) causes densely distributed clustered complex DNA damage (2). With increasing linear energy transfer (LET) (3), the density of clustered DNA damage increases markedly (4), while the reduction in radiation toxicity to healthy tissues is observed (5). However, the relative biological effectiveness (RBE) improves substantially (6). The cell killing and tumor control by high-LET RT are threatened by numerous molecular mechanisms (7). The possible mechanisms could be mutations incorporation, slow repair and altered cell cycle regulation, replication gap suppression (RGS), reversal or slow fork progression, translesion synthesis (TLS), epithelial‐mesenchymal transition (EMT) activation, release of exosomes, and epigenetic changes, which might confer radioresistance to tumor cells against high-LET RT, and may potentially, reduce the effectiveness of high-LET RT