1. Nat. Rev. Urol. doi:10.1038/nrurol.2017.179
Figure 1 Potentially actionable mutations are frequent in bladder cancer
Figure 1 | Potentially actionable mutations are frequent in bladder cancer. The Cancer Genome Atlas (TCGA) revealed numerous recurrent mutations, copy number variations, and altered expression patterns in bladder cancers that are predicted to confer sensitivity to targeted therapy28. These molecular alterations are referred to as actionable alterations, as they might be useful in therapeutic decision making. The percentages shown for different targets represent the proportion of urothelial carcinomas identified by TCGA that have actionable alterations in these genes or pathways. Changes in the RTK–MAPK pathway and the PI3K–AKT–MTOR pathway are known to confer sensitivity to therapies targeting these pathways in numerous cancer types, and many small-molecule inhibitors and monoclonal antibodies have been approved. Unfortunately, RTK and MAPK pathway inhibitors have had limited efficacy in patients with bladder cancer to date213. The emerging deeper understanding of how complex molecular features affect therapeutic sensitivity will hopefully improve response prediction. The TCGA study in bladder cancer identified varying frequencies of potentially actionable alterations in the RTK–MAPK and PI3K–AKT–MTOR signalling pathways28. Tumours with these alterations might respond to different classes of targeted treatments comprising both small-molecule inhibitors and monoclonal antibodies. Extensive crosstalk exists between these pathways (dashed lines)214. Compensatory signalling and activation of bypass signalling pathways are common mechanisms underlying both intrinsic and acquired resistance to targeted therapies. The use of combination therapies established on findings of studies focused on defining these resistance mechanisms215 might improve both the frequency and duration of response to targeted agents. Several strategies for targeting mutations in chromatin modifiers also exist. AKT, RAC serine-threonine-protein kinase; EGFR, epidermal growth factor receptor; ERK, mitogen-activated protein kinase; FGFR, fibroblast growth factor receptor; HDAC, histone deacetylase; HER2, receptor tyrosine-protein kinase ERBB2; MAPK, mitogen-activated protein kinase; MEK, dual-specificity mitogen-activated protein kinase kinase; MTOR, mechanistic target of rapamycin; PDGFR, platelet-derived growth factor receptor; PI3K, phosphoinositide 3-kinase; PTEN, phosphatase and tensin homologue; RAF, RAF proto-oncogene serine/threonine-protein kinase; RAS, GTPase RAS; ROS1, proto-oncogene tyrosine-protein kinase ROS; RTK, receptor tyrosine kinase; TSC1, hamartin; TSC2, tuberin; V600E, BRAFV600E mutation; VEGFR, vascular endothelial growth factor receptor; WT, wild type.
Felsenstein, K. M. & Theodorescu, D. (2017) Precision medicine for urothelial bladder cancer: update on tumour genomics and immunotherapy
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