Targeting cancer with kinase inhibitors

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.

Figure 3. Potential therapeutic combinations to overcome resistance to BRAF inhibitors.

Dual blockade within the MAPK pathway or between the MAPK and parallel PI3K pathways improves clinical outcome by reducing compensatory signaling and delaying the onset of resistance. Mut, mutation; OE, overexpression; LOH, loss of heterozygosity; ↓Exp, decreased expression.

Figure 2. Activating genomic alterations of protein and lipid kinases.

(A) Activating point mutations in genes coding for kinases lead to the expression of a constitutively activated kinase. Such mutations either lead to an amino acid substitution in the catalytic site, rendering it active; or change the general properties of the protein, for instance by disrupting the interaction with negative regulators, by releasing a mechanism of autoinhibition within the kinase itself, or by inducing constitutive dimerization. Last, they can cause changes in the splicing of the mRNA. Point mutations are the most common mechanism of kinase activation. (B) Chromosomal amplification of a region containing a kinase leads to its increased transcription and the production of an increased amount of protein in the cell. Consequently, the downstream pathway becomes overactivated. (C) Chromosomal alterations such as translocations or deletions can localize a kinase gene in proximity to another gene and lead to the expression of a constitutively activated chimeric or truncated kinase, or deregulate the expression of the kinase by putting it under the control of another promoter.

Figure 1. Regulation of tumorigenic programming by activation of kinases.

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.