Targeting the BMK1 MAP kinase pathway in cancer therapy

Abstract

The big mitogen activated protein kinase 1 (BMK1) pathway is the most recently discovered and least-studied mammalian mitogen-activated protein (MAP) kinase cascade, ubiquitously expressed in all types of cancer cells tested so far. Mitogens and oncogenic signals strongly activate this cellular MAP kinase pathway, thereby passing down proliferative, survival, chemoresistance, invasive, and angiogenic signals in tumor cells. Recently, several pharmacologic small molecule inhibitors of this pathway have been developed. Among them, the BMK1 inhibitor XMD8-92 blocks cellular BMK1 activation and significantly suppresses tumor growth in lung and cervical tumor models and is well tolerated in animals. On the other hand, MEK5 inhibitors, BIX02188, BIX02189, and compound 6, suppress cellular MEK5 activity, but no data exist to date on their effectiveness in animals.

Figure 1

The activated BMK1 MAPK cascade promotes cell cycle progression of tumor cells induced by mitogens and/or oncogenic signals. The BMK1 pathway is activated by mitogens and oncogenic signals through a three-level kinase cascade (MEKK2 or MEKK3/MEK5/BMK1). Subsequently, activated BMK1 phosphorylates and suppresses the activity of its downstream effector PML thereby promoting the S phase entry of tumor cells. Some tumor cells upregulate BMK1 activity by overexpression of MEK5, which consequently augments their metastatic and chemo-resistant potentials. In mitotic tumor cells, it was reported that CDK is involved in phosphorylating and regulating BMK1 in a MEK5-independent manner. PML-NB: PML-Nuclear Body.