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.
Key points
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Targeted anticancer agents are commonly used in the treatment of various solid and haematological malignancies.
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Not all tumours are sensitive to these agents, largely reflecting the lack of or inactivity of the targetable alteration.
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Radiotherapy is also frequently used for the treatment of cancer, owing to its prominent cytostatic and cytotoxic effects on malignant cells.
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A wide panel of cytoprotective pathways can be activated by radiotherapy, thus limiting therapeutic efficacy.
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However, these signal transduction cascades can be effectively inhibited with targeted anticancer agents, potentially supporting superior treatment efficacy.
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Radiotherapy stands out as a promising tool to elicit clinically actionable signalling pathways in cancer.
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Change history
18 February 2022
A Correction to this paper has been published: https://doi.org/10.1038/s41571-022-00611-7
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Acknowledgements
The work of L.C.C. is supported by US National Institutes of Health (NIH) P01 (#P01CA120964) and R35 (#R35CA197588) grants. The work of S.C.F. is supported by a Breakthrough Level 2 grant from the US Department of Defense (DoD), Breast Cancer Research Program (BRCP) (#BC180476) and by the 2019 Laura Ziskin Prize in Translational Research (#ZP-6177) from Stand Up to Cancer (SU2C). The work of L.G. is supported by a Breakthrough Level 2 grant from the US DoD BRCP (#BC180476P1), by the 2019 Laura Ziskin Prize in Translational Research (#ZP-6177, PI: Formenti) from SU2C, by a Mantle Cell Lymphoma Research Initiative (MCL-RI, PI: Chen-Kiang) grant from the Leukaemia and Lymphoma Society (LLS), by a startup grant from the Department of Radiation Oncology at Weill Cornell Medicine (New York, USA), by a Rapid Response Grant from the Functional Genomics Initiative (New York, USA), by industrial collaborations with Lytix (Oslo, Norway) and Phosplatin (New York, USA), and by donations from Phosplatin (New York, USA), the Luke Heller TECPR2 Foundation (Boston, USA), Onxeo (Paris, France), Ricerchiamo (Brescia, Italy) and Sotio a.s. (Prague, Czech Republic).
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L.G. and S.C.F. conceived the article. G.P. and L.G. wrote the first version of the manuscript with critical input from L.C.C., L.S. and S.C.F. G.P. prepared display items under supervision from L.G. All authors approve the final version of the article.
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L.S. has received research funding from Puretech. L.C.C. has acted as a consultant and/or advisor to Agios Pharmaceuticals, Faeth Therapeutics, Larkspur Therapeutics and Volastra Therapeutics, has received research funding from Petra Pharmaceuticals and is a co-founder of, and holds equity in, Agios Pharmaceuticals, Faeth Therapeutics, Larkspur Therapeutics and Volastra Therapeutics. S.C.F. has acted as a consultant and/or advisor to AstraZeneca, Bayer, Bristol Myers Squibb, Eisai, Elekta, EMD Serono, GlaxoSmithKline, Janssen, MedImmune, Merck US, Regeneron, Varian and ViewRay, and has received research funding from Bristol Myers Squibb, Eli-Lilly, Merck, Regeneron and Varian; and other support from Pfizer. L.G. has acted as a consultant and/or advisor to AstraZeneca, Boehringer Ingelheim, Inzen, The Longevity Labs, the Luke Heller TECPR2 Foundation, OmniSEQ and Onxeo, and has received research funding from Lytix, and Phosplatin. G.P. declares no competing interests.
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Petroni, G., Cantley, L.C., Santambrogio, L. et al. Radiotherapy as a tool to elicit clinically actionable signalling pathways in cancer. Nat Rev Clin Oncol 19, 114–131 (2022). https://doi.org/10.1038/s41571-021-00579-w
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DOI: https://doi.org/10.1038/s41571-021-00579-w
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