The Biology and Clinical Development of MEK Inhibitors for Cancer

Abstract

The mitogen-activated protein kinase kinases (MAPKK) MEK1 and MEK2 are integral members of the MAPK/ERK signaling pathway and are of interest in the development of anti-cancer therapeutics. The MAPK/ERK pathway is dysregulated in more than 30 % of cancers, predominately by mutations in RAS and BRAF proteins, and MEK serves as a potential downstream target for both of these. The biology of MEK inhibition is complex, as the molecule is differentially regulated by upstream RAS or RAF. This has impacted on the past development of MEK inhibitors as treatments for cancer and may be exploited in more rational, molecularly selected drug development plans in the future. The role of MEK in cancer and the mechanism of action of MEK inhibitors is reviewed. Furthermore, MEK inhibitors that are available in standard practice, as well as those most advanced in clinical development, are discussed. Finally, next steps in the development of MEK inhibitors are considered.

MEK inhibitor-associated retinopathy (MEKAR) in metastatic melanoma: Long-term ophthalmic effects

“…The T max of binimetinib is about 1.18 hours and plasma half-life 8 hours. The corresponding half-lifes for cobimetinib and trametinib are approximately 2 days (49 hours) and 4.5 days (108 hours), respectively [4]. These characteristics might highly influence the incidence of adverse events, including retinopathy (the detection is dependent on the time point of examination).…”

“…Sensitivity to MEK inhibitors has been demonstrated as monotherapy or in combination in different cancer types. Moreover, tumour control in patients has been shown in clinical studies [2][3][4][5][6][7]. The introduction of novel treatment strategies such as targeted therapy and immunomodulation have prolonged patient survival in metastatic melanoma [8][9][10][11].…”

FDA-approved small-molecule kinase inhibitors

“…Along the MAPK pathway, MEK is another target for which a considerable number of small-molecule inhibitors have been identified [85], including the only approved molecule, trametinib (Mekinist1, GlaxoSmithKline) ( Figure 12A). Trametinib was developed based on a high-throughput screening (HTS) hit that bears the same pyridopyrimidinetrione core.…”

Emerging Systemic Therapies for Colorectal Cancer

“…The mitogen-activated protein kinase kinases MEK1 and MEK2 are of considerable interest in colon cancer. 49 The majority of the clinical trials currently recruiting patients are using MEK inhibition in combination with other systemic therapies (►Table 2). A phase I study of the MEK inhibitor binimetinib (MK162) in combination with FOLFOX chemotherapy has been conducted.…”