Radiotherapy as a tool to elicit clinically actionable signalling pathways in cancer

Abstract

A variety of targeted anticancer agents have been successfully introduced into clinical practice, largely reflecting their ability to inhibit specific molecular alterations that are required for disease progression. However, not all malignant cells rely on such alterations to survive, proliferate, disseminate and/or evade anticancer immunity, implying that many tumours are intrinsically resistant to targeted therapies. Radiotherapy is well known for its ability to activate cytotoxic signalling pathways that ultimately promote the death of cancer cells, as well as numerous cytoprotective mechanisms that are elicited by cellular damage. Importantly, many cytoprotective mechanisms elicited by radiotherapy can be abrogated by targeted anticancer agents, suggesting that radiotherapy could be harnessed to enhance the clinical efficacy of these drugs. In this Review, we discuss preclinical and clinical data that introduce radiotherapy as a tool to elicit or amplify clinically actionable signalling pathways in patients with cancer.

Fig. 1 ∣. Cytoprotective pathways elicited by radiotherapy.

Ionizing radiation damages a variety of macromolecules including nuclear DNA, either directly or upon generation of reactive oxygen species. Such damage is often detected by a molecular complex encompassing meiotic recombination 11 (MRE11), DNA repair protein Rad50 (RAD50) and Nijmegen breakage syndrome 1 (NSB1) in co-operation with members of the poly(ADP-ribose) polymerase (PARP) protein family. Formation of this complex results in the sequential activation of ATM, CHEK2 and p53. Alternatively or concomitantly, the DNA damage induced by radiotherapy drives the activation of ATR and consequently CHEK1, DNA-dependent protein kinase (DNA-PK) or WEE1 signalling. Ultimately, these pathways converge on the inhibition of cyclin-dependent kinases (CDKs) resulting in arrested cell-cycle progression at specific checkpoints, which enables DNA repair and hence supports radioresistance (part a). The DNA damage response elicited by radiotherapy also promotes (directly or indirectly) the hyperactivation of PI3K signalling, resulting in the delivery of cytoprotective signals via AKT1 and MTOR (part b), the activation of autophagy (which is generally under negative regulation by MTOR) (part c), as well as the synthesis, secretion and activation of transforming growth factor-β1 (TGFβ1) (part d). GPCR, G-protein-coupled receptor; LAP, latency associated peptide; LTBP1, latent transforming growth factor-β binding protein 1; PTEN, phosphatase and tensin homologue; RTK, receptor tyrosine kinase.

Fig. 2 ∣. Targeting the pro-survival pathways induced by radiotherapy in cancer.

At least in part owing to intratumoural heterogeneity, radiotherapy alone is often unable to kill all malignant cells and thus does not mediate complete tumour eradication. In this setting, cancer cells generally resist the cytostatic and/or cytotoxic effects of radiotherapy along with the activation of various cytoprotective signalling pathways. Importantly, such cytoprotective pathways establish a state of non-oncogene addition that can be targeted using specific agents in order to achieve superior disease control.