The kinome 'at large' in cancer

Abstract

Over the past decade, rapid advances in genomics, proteomics and functional genomics technologies that enable in-depth interrogation of cancer genomes and proteomes and high-throughput analysis of gene function have enabled characterization of the kinome 'at large' in human cancers, providing crucial insights into how members of the protein kinase superfamily are dysregulated in malignancy, the context-dependent functional role of specific kinases in cancer and how kinome remodelling modulates sensitivity to anticancer drugs. The power of these complementary approaches, and the insights gained from them, form the basis of this Analysis article.

Comparative oncogenomics identifies tyrosine kinase FES as a tumor suppressor in melanoma

“…However, protein kinases exert pleiotropic functions, such as increased survival, progression of the cell cycle, differentiation, adherence, or migration, that are dependent on the tissue and molecular environment of the cells. Ultimately, this implies a context-dependent functional role of specific kinases in cancer, i.e., oncogene or TSG function (53). Our data provide an additional example of a tyrosine kinase that acts as a tumor suppressor.…”

Phosphoproteomic Profiling Reveals ALK and MET as Novel Actionable Targets across Synovial Sarcoma Subtypes

“…2C). Importantly, these aberrant ALK proteins in Aska-SS were detected using (14). C, ALK expression and phosphorylation in SS cell lines.…”

“…Next, tyrosine kinases (TK) were extracted from the original dataset, as these represent an important class of oncogenes and druggable targets (14). This resulted in the identification of 132 phosphotyrosine peptides belonging to 41 TKs, including 26 receptor tyrosine kinases (RTK) and 15 nonreceptor TKs (Supplementary Table S4).…”

“…Therefore, mutation screening to select non-GIST sarcoma patients for targeted therapy has not led to clinical benefit so far (1,10,11). Regarding protein biomarkers, most studies to date have focused on total protein expression levels, while specific screening for phosphorylation status or other read-outs of activation state may provide more accurate information regarding the pathway dependency of tumor cells and likely therapeutic benefit (2,(12)(13)(14). To this end, we characterized tyrosine kinase signaling networks in a large panel of sarcoma cell lines (n ¼ 20).…”

Small-Molecule Screens: A Gateway to Cancer Therapeutic Agents with Case Studies of Food and Drug Administration–Approved Drugs

“…This does not imply that screening centers have focused on the same molecular targets of approved drugs. For instance, recent genomic studies identified 91 protein kinases as "cancer drivers," only 22% of which are targeted by FDA-approved therapies (Fleuren et al, 2016). Indeed a substantial focus by screening centers on the primary target class, transferase, is apparent, and kinases represent the majority of targets in that class (Table 2).…”