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. Targeted therapies have improved the outcomes of many patients with cancer, although many more lack targetable alterations or do not derive clinical benefit for other reasons. Radiotherapy can also provide benefit to many patients, although radioresistance often limits the effectiveness of this intervention. Here, the authors describe the potential for radiotherapy to promote non-oncogene dependence on targetable signalling pathways, thus extending the benefits of both targeted therapy and radiotherapy to greater numbers of patients. Targeted anticancer agents are commonly used in the treatment of various solid and haematological malignancies. Not all tumours are sensitive to these agents, largely reflecting the lack of or inactivity of the targetable alteration. Radiotherapy is also frequently used for the treatment of cancer, owing to its prominent cytostatic and cytotoxic effects on malignant cells. A wide panel of cytoprotective pathways can be activated by radiotherapy, thus limiting therapeutic efficacy. However, these signal transduction cascades can be effectively inhibited with targeted anticancer agents, potentially supporting superior treatment efficacy. Radiotherapy stands out as a promising tool to elicit clinically actionable signalling pathways in cancer.