Novel ERK Inhibitor Shows Preclinical Promise Against BRAF, MEK-associated Drug Resistance

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(ChemotherapyAdvisor) – The novel extracellular signal regulated kinases 1 and 2 (ERK 1/2) inhibitor SCH772984 shows promise against tumor growth driven by BRAF and RAS mutations and might prove useful against tumor resistance to BRAF and MEK inhibitors, according to preclinical data presented at the American Association for Cancer Research (AACR) Annual Meeting 2013, in Washington, DC.

“The MAPK pathway has been the subject of intense research to develop inhibitors against components of the pathway for the treatment of cancer,” said team leader Ahmed Samatar, PhD, of the Merck Research Laboratories in Boston, MA. Vemurafenib and dabrafenib, which are selective BRAF inhibitors, and the allosteric MEK inhibitor trametinib, all exhibit “robust”—but in most cases, transient—clinical efficacy among patients diagnosed with melanoma, Dr. Samatar noted.

“Unfortunately, tumor responses are often transient and resistance to therapy is commonly associated with pathway reactivation involving the downstream module ERK1/2,” he explained.

In the MAPK pathway, ERK proteins function downstream of RAS, BRAF, and MEK, and development of BRAF and MEK inhibitor resistance is primarily driven by ERK reactivation.

To test whether or not pathway blockade at ERK can inhibit tumor growth driven by upstream BRAF or RAS mutations, Dr. Samatar and his colleagues conducted preclinical testing of SCH772984, a selective ATP competitive inhibitor that is a member of a new class of ERK protein-targeting drugs that are under development at Merck.

SCH772984 inhibited MAPK signaling and cultured human tumor cell proliferation in cells that were BRAF and MEK inhibitor-resistant, his team reported.

“Importantly, SCH772984 effectively inhibited MAPK signaling and cell proliferation in BRAF or MEK inhibitor resistance models as well as in the context of BRAF/MEK combination resistance,” Dr. Samatar and his coauthors noted.

SCH772984 was also associated with tumor regression in xenografted mice “at tolerated doses,” the team reported.

“Together these data support the clinical development of ERK inhibitors, not only in patients with MAPK-activated tumors, but also in patients who have developed acquired resistance to BRAF or MEK inhibitors or resistance to the recently described combination of these agents,” Dr. Samatar's team reported.

A phase 1 clinical trial “of an investigational ERK inhibitor” has therefore been initiated for patients with solid tumors, they reported.

“ERK inhibitors may provide a means to treat patients with these drug-resistant tumors, and an ERK inhibitor in combination with a BRAF or MEK inhibitor may also provide a strategy for overcoming drug resistance,” Dr. Samatar and his coauthors concluded.

Abstract (#2343)

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