Five MEK-Related Questions for Jeffrey S. Weber, MD, PhD

Jeffrey S. Weber, MD, PhD

Director, Donald A. Adam Comprehensive Melanoma Research Center, Moffitt Cancer Center and Research Institute, Tampa, FL

Jeffrey S. Weber, MD, PhD, specializes in cancer immunotherapy and has been involved in numerous trials of clinical drug development, vaccines, and studies on autoimmunity and melanoma. He is principal investigator on several National Cancer Institute (NCI)-funded studies, has published more than 100 articles in top peer-reviewed journals, and has served on various boards, including the NCI’s Clinical Oncology Study Section, the US Department of Veterans Affairs’ Clinical Oncology Study Section, and the scientific advisory boards of four cancer-related biotechnology companies.

1

What is MEK?

MAPK/ERK kinase (MEK) is a protein that adds phosphate groups to, and thus regulates, the activity of mitogenactivated protein kinases (MAPKs). It is otherwise known as a MAP kinase kinase. It belongs to a class of molecule that is involved in a cascade that transmits a signal after binding of growth factors to a surface receptor, and then helps to promote a series of events that cause increased transcription and expression of genes important for cell growth and proliferation. MEK is far downstream in the MAP kinase pathway, downstream of Ras and Raf signaling.

2

How is MEK signaling implicated in the development of cancer?

The MAPK signaling pathway is important for the growth, survival, and spread of a number of cancers but plays a particularly important role in melanoma. Blocking it with drugs has been quite successful at causing shrinkage of melanoma. Blocking BRAF, a molecule in the MAPK signaling cascade upstream of MEK, or MEK itself, can cause melanomas to shrink.

3

What MEK-targeted agents are currently available or in development as cancer therapeutics?

The drug trametinib from GlaxoSmithKline has been tested in a head-to-head comparison in a randomized phase III study compared with a chemotherapy drug. It was found to prolong survival, and also had a better time to progression than the chemotherapy drug. These data were presented at the major clinical oncology meeting in June in Chicago [American Society of Clinical Oncology] and published soon thereafter by the prestigious New England Journal of Medicine. Another drug, MEK 162, is being tested by Novartis in earlier-stage trials.

4

What has been the most significant advance in the field of MEK-targeted cancer therapy in recent years?

The positive result of the single-agent trametinib trial noted above has been a major advance in establishing the unequivocal clinical benefit of a MEK inhibitor for patients with cancer. Further evidence of benefit to patients with a MEK inhibitor came from the report, also at the meeting in Chicago in June 2012, of results from a phase I/II trial of the MEK inhibitor trametinib, combined with the BRAF inhibitor dabrafenib. In the trial, there was evidence that the toxicities of either agent alone were decreased with the combination, and there was also preliminary evidence that, at the highest doses of the combination, clinical benefit was increased compared with either drug alone. The time to progression was 10.8 months in patients who received the highest dose of the combination, which was well tolerated, compared with 6-7 months for the BRAF inhibitor or 4-5 months for the MEK inhibitor.

5

What is the future of MEK-targeted cancer therapy?

The MEK inhibitors are currently being evaluated in patients who have NRAS mutations and cannot benefit from BRAF inhibitors. The MEK inhibitors will be added to BRAF inhibitors, and will also be used in novel triplecombination regimens of BRAF plus MEK plus phosphatidylinositol- 3-kinase (PI3K) or Akt inhibitors. MEK inhibitors will also be added to other, more novel inhibitors that may augment their effectiveness in melanoma and other cancers, especially those that are mutated in BRAF.