Directly targeting transcriptional dysregulation in cancer.
Drugs that target intracellular signalling pathways have markedly improved progression-free survival of patients with cancers who were previously regarded as untreatable. However, the rapid emergence of therapeutic resistance, as a result of bypass signalling or downstream mutation within kinase-mediated signalling cascades, has curtailed the benefit gained from these therapies. Such resistance mechanisms are facilitated by the linearity and redundancy of kinase signalling pathways. We argue that, in each cancer, the dysregulation of key transcriptional regulators not only defines the cancer phenotype but is essential for its development and maintenance. Furthermore, we propose that, as therapeutic targets, these transcriptional regulators are less prone to bypass by alternative mutational events or clonal heterogeneity, and therefore we must rekindle our efforts to directly target transcriptional regulation across a broad range of cancers.
School of Pharmacy, University of Queensland, Pharmacy Australia Centre of Excellence (PACE), 20 Cornwall Street, Woolloongabba, Queensland 4102, Australia.
Thomas J
TJ
Gonda
Peter MacCallum Cancer Centre and the Sir Peter MacCallum Oncology Department and the Pathology Department, University of Melbourne, Parkville, Victoria 3010, Australia.
Robert G
RG
Ramsay
D000970:Antineoplastic Agents / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000235:genetics*; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics*; D015398:Signal Transduction / Q000187:drug effects*
D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor