Preclinical study indicates potential for novel inhibitor to overcome drug resistance induced by RAF, MEK inhibitors

A new class of investigational medicines may help to treat patients with cancers driven by mutations in genes such as BRAF or KRAS/NRAS, including those patients who have become resistant to therapies that target BRAF directly, according to preclinical data presented at the AACR Annual Meeting 2013, held in Washington, D.C., April 6-10.

These new drugs, which are being developed by Merck, target ERK proteins. ERK proteins are components of the MAPK signaling pathway. In this pathway, they function downstream of RAS, and MEK. Inhibitors of BRAF and MEK have shown clinical efficacy in patients with melanoma harboring BRAF gene mutations.

"The MAPK pathway has been the subject of intense research to develop inhibitors against components of the pathway for the ," said Ahmed Samatar, Ph.D., team leader of discovery oncology at Merck Research Laboratories. "Unfortunately, tumor responses are often transient and resistance to therapy is commonly associated with pathway reactivation involving the downstream module ERK1/2."

Samatar and colleagues hypothesized that inhibiting ERK in tumor cells driven by an activated MAPK pathway, as a result of either BRAF or RAS mutations, could provide a means of inhibiting tumor cell growth. The researchers used SCH772984, a novel ERK inhibitor, to test this theory.

Their results indicated that SCH772984 was a potent inhibitor of ERK1/2 in cultured human tumor cells with mutations in BRAF, NRAS or KRAS. The drug also induced when tested in mouse models.

In addition, SCH772984 inhibited MAPK signaling and in human tumor cells resistant to BRAF and MEK inhibitors alone or in combination.

"Patients with cancer treated with BRAF and/or MEK inhibitors are susceptible to the development of resistance primarily via reactivation of ERK," Samatar said. "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 to overcome drug resistance."

Samatar and colleagues have initiated a phase I clinical trial of an investigational ERK inhibitor in patients with solid tumors.

add to favorites email to friend print save as pdf

Related Stories

Combination therapies for drug-resistant cancers

Oct 10, 2011

Some cancers can be effectively treated with drugs inhibiting proteins known as receptor tyrosine kinases, but not those cancers caused by mutations in the KRAS gene. A team of researchers led by Jeffrey Engelman, at Massachusetts ...

Recommended for you

Why we should vaccinate boys against HPV as well as girls

1 hour ago

Gillian Prue, from the School of Nursing and Midwifery at Queen's University of Belfast, says that the human papillomavirus (HPV) infection is common in men and can lead to genital warts and the development of some head and ...

Generation of tanners see spike in deadly melanoma

13 hours ago

(AP)—Stop sunbathing and using indoor tanning beds, the acting U.S. surgeon general warned in a report released Tuesday that cites an alarming 200 percent jump in deadly melanoma cases since 1973.

Penn team makes cancer glow to improve surgical outcomes

13 hours ago

The best way to cure most cases of cancer is to surgically remove the tumor. The Achilles heel of this approach, however, is that the surgeon may fail to extract the entire tumor, leading to a local recurrence.

User comments