SMK-17, a MEK1/2-specific inhibitor, selectively induces apoptosis in β-catenin-mutated tumors

Abstract

Although clinical studies have evaluated several MEK1/2 inhibitors, it is unlikely that MEK1/2 inhibitors will be studied clinically. BRAF mutations have been proposed as a responder marker of MEK1/2 inhibitors in a preclinical study. However, current clinical approaches focusing on BRAF mutations have shown only moderate sensitivity of MEK1/2 inhibitors. This has led to insufficient support for their promoted clinical adoption. Further characterization of tumors sensitive to MEK inhibitors holds great promise for optimizing drug therapy for patients with these tumors. Here, we report that β-catenin mutations accelerate apoptosis induced by MEK1/2 inhibitor. SMK-17, a selective MEK1/2 inhibitor, induced apoptosis in tumor cell lines harboring β-catenin mutations at its effective concentration. To confirm that β-catenin mutations and mutant β-catenin-mediated TCF7L2 (also known as TCF4) transcriptional activity is a predictive marker of MEK inhibitors, we evaluated the effects of dominant-negative TCF7L2 and of active, mutated β-catenin on apoptosis induced by MEK inhibitor. Indeed, dominant-negative TCF7L2 reduced apoptosis induced by MEK inhibitor, whereas active, mutated β-catenin accelerated it. Our findings show that β-catenin mutations are an important responder biomarker for MEK1/2 inhibitors.

Mitochondrial uncoupler exerts a synthetic lethal effect against β‐catenin mutant tumor cells

“…APC is a negative regulator of the Wnt signaling pathway, and the truncated mutations of APC fail to form a scaffold for the destruction complex, leading to stabilized β‐catenin and an aberrantly activated Wnt signaling pathway . Moreover, stimulation of β‐catenin wild type A375 cells with Wnt‐3a enhanced the ability of SMK‐17 to induce apoptosis in β‐catenin wild type A375 cells, as previously reported . However, nonactin failed to induce apoptosis in A375 cells even after stimulation with Wnt‐3a (Fig.…”

“…We have previously reported that MEK1/2 inhibitors induce cell growth arrest in β‐catenin wild type tumor cell lines, whereas they induce apoptosis in β‐catenin mutant tumor cell lines in vitro . Furthermore, we have reported that a MEK inhibitor alone could induce significant tumor regression in β‐catenin‐mutant xenograft models . These findings support the clinical use of MEK inhibitors as single agents for patients with colorectal carcinoma who carry active β‐catenin mutations.…”

“…Furthermore, we have reported that a MEK inhibitor alone could induce significant tumor regression in b-cateninmutant xenograft models. (24) These findings support the clinical use of MEK inhibitors as single agents for patients with colorectal carcinoma who carry active b-catenin mutations. To find another effective compound that is effective for patients with tumors who carry active b-catenin mutations, we screened for compounds that exhibited synthetic lethality with b-catenin mutations, other than MEK1/2, from an in-house natural product library.…”

“…This outcome indicates that nonactin induced apoptosis in HCT 116 cells at least 100 times more effectively than in A375 cells. We have previously reported that MEK1/2 inhibitors induced apoptosis selectively in β‐catenin mutant tumor cell lines . However, nonactin did not inhibit ERK1/2 phosphorylation in either cell line (Fig.…”

“…A431 cells were provided by M. Kawada (Institute of Microbial Chemistry, Japan). The other cell lines were obtained from the ATCC (Rockville, MD, USA) . A431 cells were maintained in Dulbecco's modified eagle medium (DMEM) supplemented with 5% calf serum (CS), 100 U/mL penicillin G (Sigma‐Aldrich), and 0.1 mg/mL kanamycin (Sigma‐Aldrich) at 37°C in a humidified atmosphere containing 5% CO 2 .…”