Abstract
The MYC proto-oncogenes encode a family of transcription factors that are among the most commonly activated oncoproteins in human neoplasias. Indeed, MYC aberrations or upregulation of MYC-related pathways by alternate mechanisms occur in the vast majority of cancers. MYC proteins are master regulators of cellular programmes. Thus, cancers with MYC activation elicit many of the hallmarks of cancer required for autonomous neoplastic growth. In preclinical models, MYC inactivation can result in sustained tumour regression, a phenomenon that has been attributed to oncogene addiction. Many therapeutic agents that directly target MYC are under development; however, to date, their clinical efficacy remains to be demonstrated. In the past few years, studies have demonstrated that MYC signalling can enable tumour cells to dysregulate their microenvironment and evade the host immune response. Herein, we discuss how MYC pathways not only dictate cancer cell pathophysiology but also suppress the host immune response against that cancer. We also propose that therapies targeting the MYC pathway will be key to reversing cancerous growth and restoring antitumour immune responses in patients with MYC-driven cancers.
Key points
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The MYC oncogene is activated in the vast majority of cancers by genetic, epigenetic or post-translational mechanisms.
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In preclinical models, inactivation of MYC can result in sustained tumour regression owing to oncogene addiction.
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MYC activation drives cancer progression through mechanisms involving either the cell-intrinsic acquisition of hallmarks of cancer or dysregulation of the tumour microenvironment and host immune responses.
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MYC leads to cancer initiation and maintenance by regulating the host immune system through mechanisms involving immune checkpoints, specific receptors and secreted cytokines.
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Currently, no direct inhibitors of MYC are approved; however, many therapeutic agents targeting MYC are under development.
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We propose that therapies targeting the MYC pathway will be key to reversing cancerous growth and restoring antitumour immune responses in patients with MYC-driven cancers.
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Acknowledgements
R.D. receives grant support from the NIH (grant CA222676). A.D. has received support from Lymphoma Research Foundation. A.S.H. has received support from Lundbreck Foundation. A.M.G. has received support from the NIH (grant CA196585). D.W.F. receives grant support from the NIH (grants CA208735, CA253180, CA188383 and CA184384).
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R.D. and D.W.F. researched data for this manuscript. All authors contributed to the discussion of content and preparation of the manuscript.
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D.W.F. is a consultant for Revolution Medicines, a company developing MYC pathway therapies, co-founder of Bachus and Molecular Decisions, and has had advisory roles for American Gene Technologies, Geron, Moderna and Regulus. The other authors declare no conflicts of interest.
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Dhanasekaran, R., Deutzmann, A., Mahauad-Fernandez, W.D. et al. The MYC oncogene — the grand orchestrator of cancer growth and immune evasion. Nat Rev Clin Oncol 19, 23–36 (2022). https://doi.org/10.1038/s41571-021-00549-2
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DOI: https://doi.org/10.1038/s41571-021-00549-2
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