Molecular Mechanisms of Radiation-Induced Cancer Cell Death: A Primer

Abstract

Radiation therapy (RT) is responsible for at least 40% of cancer cures, however treatment resistance remains a clinical problem. There have been recent advances in understanding the molecular mechanisms of radiation-induced cell death. The type of cell death after radiation depends on a number of factors including cell type, radiation dose and quality, oxygen tension, TP53 status, DNA repair capacity, cell cycle phase at time of radiation exposure, and the microenvironment. Mitotic catastrophe (a pathway preceding cell death that happens in mitosis or as a consequence of aberrant mitotic progression) is the primary context of radiation-induced cell death in solid cancers, although in a small subset of cancers such as haematopoietic malignancies, radiation results in immediate interphase apoptosis, occurring within hours after exposure. There is intense therapeutic interest in using stereotactic ablative body radiotherapy (SABR), a precise, high-dose form of RT given in a small number of fractions, to prime the immune system for cancer cell killing, but the optimal radiation dose and fractionation remain unclear. Additionally, promising novel radiosensitisers targeting the cell cycle and DNA repair pathways are being trialled. In the context of the increasing use of SABR and such novel agents in the clinic, we provide an updated primer on the major types of radiation-induced cell death, focussing on their molecular mechanisms, factors affecting their initiation, and their implications on immunogenicity.

Keywords: abscopal effect; cell death; immunogenic cell death; radiation therapy; radiotherapy; stereotactic ablative radiotherapy.

FIGURE 1

The anti-tumour activity of radiation therapy (RT) is multi-faceted. Tumour irradiation induces both direct and indirect effects in controlling the tumour. Direct effects are the result of significant radiation-induced DNA damage in cancer cells leading to their death, which may occur at various time points after the initial irradiation event. Radiation therapy (RT) also exerts anti-tumour activity via indirect effects, which include, but are not limited to, injury of tumour vasculature and priming of host anti-tumour immune responses. A range of factors influence the triggering and magnitude of these effects, broadly falling into cell-intrinsic, radiation, and microenvironment factors. A deeper knowledge of the underpinning mechanisms and their interplay will reveal opportunities for enhancing the overall anti-tumour activity of RT. ATM, ataxia-telangiectasia mutated. DAMP, danger associated-molecular pattern.