Abstract
Despite the development of targeted therapies and novel inhibitors, cancer remains an undefeated disease. Resistance mechanisms arise quickly and alternative treatment options are urgently required, which may be partially met by drug combinations. Protein kinases as signaling switchboards are frequently deregulated in cancer and signify vulnerable nodes and potential therapeutic targets. We here focus on the cell cycle kinase CDK6 and on the MAPK pathway and on their interplay. We also provide an overview on clinical studies examining the effects of combinational treatments currently explored for several cancer types.
Highlights
Tumorigenesis requires that cells hijack regulatory networks to obtain their full oncogenic potential
While the extracellular signal-regulated kinase (ERK) pathway is predominantly activated by growth factors to drive survival and cell growth, activation of the JNK or p38 pathway is accomplished by environmental stressors and inflammatory cytokines and is associated with apoptosis and growth inhibition [1]
We here discuss the interference of CDK6 and MAPK cascades in cancer and focus on currently available inhibitors in preclinical and clinical contexts, which may open therapeutic options for combined targeted therapy
Summary
Tumorigenesis requires that cells hijack regulatory networks to obtain their full oncogenic potential. The MAPK (mitogen-activated protein kinase) pathway is a tightly regulated signaling cascade frequently mutated or deregulated in cancer. MAPK cascades are structured in three core protein kinases (MAP3K, MAP2K and MAPK), which allows a tight regulation [1] (Figure 1). Transcriptional regulation of cell cycle components by MAPKs links cyclin-dependent kinases (CDKs) to the MAP kinase cascade. MAPKs regulate the expression levels of D-type cyclins, key players of the cell cycle [2]. Changing the levels of D-type cyclins impacts on the activation of their cell cycle partners, the cyclin-dependent kinases 4 and 6 (CDK4 and CDK6). CDK4 and its close homologue CDK6 play a crucial role in various cancer types Both are part of the G1 cell cycle checkpoint and allow the cell to enter into the S-phase [3].
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