Roswell Park Comprehensive Cancer Center Researchers Review Promising Novel Approaches to MEK Inhibitor Therapy

BUFFALO, N.Y. — A review article authored by two Roswell Park Comprehensive Cancer Center experts provides a comprehensive clinical view of currently available and novel MEK inhibitors, and highlights strategies that may lead to the wider use of these agents in cancer therapy. The review is published in Nature Reviews Clinical Oncology.

Several MEK1/2 inhibitors have been developed and evaluated over the last decade. As part of the RAS-RAF-MEK-ERK (extracellular signal-regulated kinase) 1 and 2 pathway, MEK 1/2 plays a key role in tumorigenesis, cell proliferation and apoptosis inhibition in several cancer types, making it an attractive therapeutic target.

“MEK has a narrow kinase substrate specificity, which allows the development of therapeutic agents that specifically interrupt the RAS-RAF-MEK-ERK 1/2 pathway with fewer off-target side effects, and the protein structural characteristics of MEK also allow the design of highly potent and specific inhibitors,” said first author of the review Yujie Zhao, MD, PhD, a staff physician and Assistant Professor of Oncology in the Department of Medical Oncology at Roswell Park.

Despite the important role of the kinase, however, most MEK inhibitors have demonstrated only limited efficacy as single agents, failing to exhibit significant clinical activity in most of the tumor types studied, according to Dr. Zhao and senior author Alex Adjei, MD, PhD, FACP, Senior Vice President of Clinical Research and Katherine Anne Gioia Chair in Cancer Medicine at Roswell Park.

Currently, trametinib is the only MEK inhibitor that is approved by the U.S. Food and Drug Administration for clinical use as a single agent or in combination with a BRAF inhibitor dabrafenib for the treatment of BRAF-mutant melanoma. Drs. Adjei and Zhao point out several possible reasons for the lack of clinical efficacy with the other MEK inhibitors:

• There may not be high enough intra-tumor concentration of MEK inhibitors
• Other kinases may also mediate RAS-RAF-induced cancer development; activation of other cancer-related signaling pathways may prevent MEK inhibitor-induced apoptosis
• It remains unclear how to identify patients with RAS-RAF-MEK-ERK-dependent tumors
• MEK inhibition may also inhibit negative feedback pathways between MAPK and RAF, which could lead to increased RAF activity and activation of other downstream RAF targets, which may prevent cancer cell death 

Still, there are promising novel approaches to MEK inhibitor therapy that merit additional research. “Two RAF inhibitors were approved for BRAF-mutated melanoma,” Dr. Zhao said. “However, RAF inhibitors have no activity in uveal melanoma and NRAS-mutated melanoma.” MEK inhibitors demonstrated activity in these tumors and may be a potential treatment in this subset of patients.

Furthermore, in melanoma patients, BRAF inhibition may lead to cutaneous squamous-cell carcinoma, which is linked to BRAF inhibitor-induced paradoxical activation of MAPK pathway. “Dual inhibition of MEK and RAF reduced this particular toxicity and is a promising strategy in targeting the RAF-MEK-MAPK pathway,” Dr. Zhao said.

Ongoing MEK inhibitor research will continue exploring predictive biomarkers for identifying those patients who may be the most sensitive to MEK inhibition, according to Dr. Zhao. Researchers are also evaluating ways to mitigate resistance mechanisms that currently restrict the clinical utility of these agents, such as combining MEK inhibitors with other targeted therapeutic or cytotoxic agents.

“The results we’ve seen with small kinase inhibitors targeting MEK 1/2 have been encouraging, particularly in melanoma. These agents have been highly potent and, for the most part, well-tolerated,” notes Dr. Adjei. “Our analysis points out some of the challenges that face researchers working in this area, but we also highlighted several promising directions for future research.”

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The mission of Roswell Park Comprehensive Cancer Center is to understand, prevent and cure cancer. Founded in 1898, Roswell Park is one of the first cancer centers in the country to be named a National Cancer Institute-designated comprehensive cancer center and remains the only facility with this designation in Upstate New York. The Institute is a member of the prestigious National Comprehensive Cancer Network, an alliance of the nation’s leading cancer centers; maintains affiliate sites; and is a partner in national and international collaborative programs. For more information, visit www.roswellpark.org, call 1-800-ROSWELL (1-800-767-9355) or email AskRoswell@Roswellpark.org. Follow Roswell Park on Facebook and Twitter.