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Targeting cancer with kinase inhibitors
Stefan Gross, … , Christoph Lengauer, Klaus P. Hoeflich
Stefan Gross, … , Christoph Lengauer, Klaus P. Hoeflich
Published May 1, 2015
Citation Information: J Clin Invest. 2015;125(5):1780-1789. https://doi.org/10.1172/JCI76094.
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Review

Targeting cancer with kinase inhibitors

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Abstract

Kinase inhibitors have played an increasingly prominent role in the treatment of cancer and other diseases. Currently, more than 25 oncology drugs that target kinases have been approved, and numerous additional therapeutics are in various stages of clinical evaluation. In this Review, we provide an in-depth analysis of activation mechanisms for kinases in cancer, highlight recent successes in drug discovery, and demonstrate the clinical impact of selective kinase inhibitors. We also describe the substantial progress that has been made in designing next-generation inhibitors to circumvent on-target resistance mechanisms, as well as ongoing strategies for combining kinase inhibitors in the clinic. Last, there are numerous prospects for the discovery of novel kinase targets, and we explore cancer immunotherapy as a new and promising research area for studying kinase biology.

Authors

Stefan Gross, Rami Rahal, Nicolas Stransky, Christoph Lengauer, Klaus P. Hoeflich

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Figure 1

Regulation of tumorigenic programming by activation of kinases.

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Regulation of tumorigenic programming by activation of kinases.
Survival...
Survival: Kinase pathways regulate programmed cell death by either directly modulating apoptosis regulators or altering their expression. Necroptosis is controlled by signaling pathways that intersect apoptosis regulators, including RIPK3. Motility: Cytoskeletal dynamics are mediated by RTKs and integrin clustering to promote the activation of FAK and GTPases. Effector kinases include ROCK1, MLCK (encoded by MYLK3), PAK1, and LIMK1. Evading antitumor immunity: Numerous cell types, including CTLs, Tregs, DCs, MDSCs, and macrophages, are actively involved in modulating the tumor immune response. MAP4K1, PI3K∂, MST1R, MERTK, and PKCη, represent potential targets for reversing the myriad mechanisms involved in tumor-mediated immunosuppression of the tumor microenvironment. Proliferation: MAPK pathway components increase levels of CCND1. CCND1 regulates the activity of CDK4/6 and, in turn, induces cell cycle progression via RB1 and E2F transcriptional regulators. DNA damage checkpoints: Following induction of double-strand DNA breaks by ionizing radiation or chemotherapeutic agents, ATM and ATR phosphorylate CHK1. Activated CHK1 subsequently prevents cell cycle progression and induces DNA repair mechanisms. Angiogenesis: Tumor cells modulate the microenvironment by secreting angiogenic factors (ligands for VEGFR, FGFRs, and the angiopoietin receptor TIE2 [encoded by TEK]) to stimulate endothelial cells and enhance vascularization. Pericytes are in turn stimulated by PDGF and TGF growth factors to contribute to endothelial cell proliferation and migration. Metabolism: PI3K/AKT pathway activity is directly correlated with increased glucose metabolism in cancer cells. Signaling is mediated through hexokinases, MTOR, and HIF1α (encoded by HIF1A) to increase oxidative phosphorylation, tricarboxylic acid cycle, and mitochondrial respiration.
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