MEK inhibitor

A MEK inhibitor is a chemical or drug that inhibits the mitogen-activated protein kinase kinase enzymes MEK1 and/or MEK2. They can be used to affect the MAPK/ERK pathway which is often overactive in some cancers. (See MAPK/ERK pathway#Clinical significance.)

Hence MEK inhibitors have potential for treatment of some cancers,^[1] especially BRAF-mutated melanoma,^[2] and KRAS/BRAF mutated colorectal cancer.^[3]

Approved for clinical use

• Trametinib (GSK1120212), FDA-approved to treat BRAF-mutated melanoma. Also studied in combination with BRAF inhibitor dabrafenib to treat BRAF-mutated melanoma.
• Cobimetinib or XL518, approved by US FDA in Nov 2015 for use in combination with vemurafenib (Zelboraf(R)), for treatment of advanced melanoma with a BRAF V600E or V600K mutation.

In clinical trials

• Binimetinib (MEK162), is currently in phase 3 clinical trials for ovarian cancer,^[4] BRAF mutant melanoma,^[5] and NRAS mutant melanoma.^[6]
• Selumetinib, had a phase 2 clinical trial for non-small cell lung cancer (NSCLC) which demonstrated an improvement in PFS,^[7] and is now in phase III development in KRAS mutation positive NSCLC (SELECT-1, NCT01933932). Other ph 3 clinical trials underway include uveal melanoma (failed), and differentiated thyroid carcinoma.
• PD-325901, for breast cancer, colon cancer, and melanoma^[8] A phase II trial for advanced non-small cell lung cancer "did not meet its primary efficacy end point".^[9]

Others

• CI-1040, PD035901
• TAK-733, preclinical for multiple myeloma.^[10]

References

1. Wang, Ding; Boerner, Scott A.; Winkler, James D.; Lorusso, Patricia M. (2007). "Clinical experience of MEK inhibitors in cancer therapy". Biochim Biophys Acta. 1773 (8): 1248–55. doi:10.1016/j.bbamcr.2006.11.009. PMID 17194493.
2. "ASCO: MEK Inhibitors—Alone or Paired With a BRAF Inhibitor—Increase Options, Benefits for Patients With BRAF-Mutated Advanced Melanoma". 2012.
3. KRAS/BRAF mutation status and ERK1/2 activation as biomarkers for MEK1/2 inhibitor therapy in colorectal cancer. 2009
4. A Study of MEK162 vs. Physician's Choice Chemotherapy in Patients With Low-grade Serous Ovarian, Fallopian Tube or Peritoneal Cancer
5. Study Comparing Combination of LGX818 Plus MEK162 Versus Vemurafenib and LGX818 Monotherapy in BRAF Mutant Melanoma (COLUMBUS)
6. Study Comparing the Efficacy of MEK162 Versus Dacarbazine in Unresectable or Metastatic NRAS Mutation-positive Melanoma
7. Jänne, Pasi A; Shaw, Alice T; Pereira, José Rodrigues; Jeannin, Gaëlle; Vansteenkiste, Johan; Barrios, Carlos; Franke, Fabio Andre; Grinsted, Lynda; Zazulina, Victoria; Smith, Paul; Smith, Ian; Crinò, Lucio (2013). "Selumetinib plus docetaxel for KRAS-mutant advanced non-small-cell lung cancer: A randomised, multicentre, placebo-controlled, phase 2 study". The Lancet Oncology. 14 (1): 38–47. doi:10.1016/S1470-2045(12)70489-8. PMID 23200175.
8. MEK Inhibitor PD-325901 To Treat Advanced Breast Cancer, Colon Cancer, And Melanoma
9. A phase II study of PD-0325901, an oral MEK inhibitor, in previously treated patients with advanced non-small cell lung cancer. 2010
10. MEK inhibitor, TAK-733 reduces proliferation, affects cell cycle and apoptosis, and synergizes with other targeted therapies in multiple myeloma. Feb 2016