Discovery of a Novel ERK Inhibitor with Activity in Models of Acquired Resistance to BRAF and MEK Inhibitors

Abstract

The high frequency of activating RAS or BRAF mutations in cancer provides strong rationale for targeting the mitogen-activated protein kinase (MAPK) pathway. Selective BRAF and MAP-ERK kinase (MEK) inhibitors have shown clinical effi cacy in patients with melanoma. However, the majority of responses are transient, and resistance is often associated with pathway reactivation of the extracellular signal-regulated kinase (ERK) signaling pathway. Here, we describe the identifi cation and characterization of SCH772984, a novel and selective inhibitor of ERK1/2 that displays behaviors of both type I and type II kinase inhibitors. SCH772984 has nanomolar cellular potency in tumor cells with mutations in BRAF , NRAS , or KRAS and induces tumor regressions in xenograft models at tolerated doses. Importantly, SCH772984 effectively inhibited MAPK signaling and cell proliferation in BRAF or MEK inhibitor-resistant models as well as in tumor cells resistant to concurrent treatment with BRAF and MEK inhibitors. These data support the clinical development of ERK inhibitors for tumors refractory to MAPK inhibitors. SIGNIFICANCE: BRAF and MEK inhibitors have activity in MAPK-dependent cancers with BRAF or RAS mutations. However, resistance is associated with pathway alterations resulting in phospho-ERK reactivation. Here, we describe a novel ERK1/2 kinase inhibitor that has antitumor activity in MAPK inhibitor-naïve and MAPK inhibitor-resistant cells containing BRAF or RAS mutations. Cancer Discov; 3(7); 742-50.

Targeting the MAPK Signaling Pathway in Cancer: Promising Preclinical Activity with the Novel Selective ERK1/2 Inhibitor BVD-523 (Ulixertinib)

“…Binding of BVD-523 to ERK2 was demonstrated using calorimetric studies and compared with data generated using the ERK inhibitors SCH772984 (26) and pyrazolylpyrrole (31). All compounds bound and stabilized inactive ERK2 with increasing concentration, as indicated by positive DTm values (Fig.…”

“…Reactivation and dependence on ERK1/2 signaling is a common feature of acquired resistance to BRAF/MEK inhibition (26,27); therefore, we evaluated the activity of BVD-523 in in vitro models of acquired resistance. First, a dabrafenib and trametinib combination-resistant A375 population was obtained using the increased concentration method (as described in detail in Supplementary Materials and Methods section of this manuscript).…”

“…Inhibiting ERK may provide important clinical benefit to patients with acquired resistance to BRAF/MEK inhibition. ERK family kinases have shown promise as therapeutic targets in preclinical cancer models, including those resistant to BRAF or MEK inhibitors (26)(27)(28); however, the potential for ERK inhibitors expands beyond acquired resistance in melanoma.…”

ERK Pathway Inhibitors: How Low Should We Go?

“…In summary, the data reported by Morris and colleagues ( 11 ) in this issue of Cancer Discovery support the study of ATP-competitive ERK inhibitors in patients whose tumors exhibit mutational activation of the MAPK pathway. As with MEK inhibitors, the combination of RAF and ERK inhibitors may have greater antitumor effects and less toxicity than either agent alone in patients with BRAF-mutant tumors.…”

“…With the goal of addressing this unmet medical need, Morris and colleagues ( 11 ) report in this issue of Cancer Discovery the identifi cation and functional characterization of a novel, selective ERK inhibitor. The investigators initially conducted an affi nity-based screen to identify compounds that bind selectively to the unphosphorylated form of ERK2.…”