Harnessing the targeting potential of differential radiobiological effects of photon versus particle radiation for cancer treatment

Abstract Radiotherapy is one of the major modalities for malignancy treatment. High linear energy transfer (LET) charged‐particle beams, like proton and carbon ions, exhibit favourable depth‐dose distributions and radiobiological enhancement over conventional low‐LET photon irradiation, thereby marking a new era in high precision medicine. Tumour cells have developed multicomponent signal transduction networks known as DNA damage responses (DDRs), which initiate cell‐cycle checkpoints and induce double‐strand break (DSB) repairs in the nucleus by nonhomologous end joining or homologous recombination pathways, to manage ionising radiation (IR)‐induced DNA lesions. DNA damage induction and DSB repair pathways are reportedly dependent on the quality of radiation delivered. In this review, we summarise various types of DNA lesion and DSB repair mechanisms, upon irradiation with low and high‐LET radiation, respectively. We also analyse factors influencing DNA repair efficiency. Inhibition of DNA damage repair pathways and dysfunctional cell‐cycle checkpoint sensitises tumour cells to IR. Radio‐sensitising agents, including DNA–PK inhibitors, Rad51 inhibitors, PARP inhibitors, ATM/ATR inhibitors, chk1 inhibitors, wee1 kinase inhibitors, Hsp90 inhibitors, and PI3K/AKT/mTOR inhibitors have been found to enhance cell killing by IR through interference with DDRs, cell‐cycle arrest, or other cellular processes. The cotreatment of these inhibitors with IR may represent a promising therapeutic strategy for cancer.