MEK1/2 Inhibitors AS703026 and AZD6244 May Be Potential Therapies for KRAS Mutated Colorectal Cancer That Is Resistant to EGFR Monoclonal Antibody Therapy

Abstract

Epidermal growth factor receptor (EGFR) monoclonal antibodies (mAb) are used widely to treat metastatic colorectal cancer (mCRC) patients, but it is now clear that patients harboring K-ras mutation are resistant to EGFR mAbs such as cetuximab (Erbitux) and panitumumab (Vectibix). For this reason, current recommendations for patient care involve diagnosing the K-ras mutational status of patients prior to EGFR mAb therapy. In this study, we investigated the ability of two MEK inhibitors currently in clinical trials, AS703026 and AZD6244, to address the challenge posed by the resistance of K-ras mutated colorectal cancers to EGFR mAb. AS703026 and AZD6244 were tested in various cell-based assays and tumor xenograft studies, focusing on isogenic human colorectal tumor cell lines that expressed only WT or mutant K-Ras (D-WT or D-MUT). The EGFR mAb cetuximab inhibited the Ras-ERK pathway and proliferation of D-WT cells in vitro and in vivo, but it did not inhibit proliferation of D-MUT cells in either setting. In contrast, AS703026 and AZD6244 effectively inhibited the growth of D-MUT cells in vitro and in vivo by specific inhibition of the key MEK downstream target kinase ERK. Inhibition of MEK by AS703026 or AZD6244 also suppressed cetuximab-resistant colorectal cancer cells attributed to K-ras mutation both in vitro and in vivo. Our findings offer proof-of-concept for the use of MEK inhibitors as an effective therapy in K-ras mutated CRC. Cancer Res; 71(2); 445-53. Ó2010 AACR.

Inhibition of MEK and PI3K/mTOR Suppresses Tumor Growth but Does Not Cause Tumor Regression in Patient-Derived Xenografts of RAS-Mutant Colorectal Carcinomas

“…Preclinical studies in KRAS-mutant colorectal cell lines have shown that individual blockade of MEK or combined inhibition of MEK and mTOR induce cell-cycle arrest and/or (29,30). Accordingly, we observed that pharmacologic neutralization of MEK and PI3K/mTOR suppressed growth in a high percentage of mCRC patient-derived xenografts, an effect that was magnified by further addition of cetuximab.…”

Molecular pathology of lung cancer: key to personalized medicine

“…56,216 The histological phenotype of BRAF mutant adenocarcinomas has not been well described, but was reported to be a mixed type adenocarcinoma with a high incidence of papillary (80%) and lepidic growth (50%) patterns. 217 De Oliveira Duarte Achcar et al 218 investigated 15 primary micropapillary lung adenocarcinomas for KRAS, EGFR, and BRAF mutations.…”

The MEK1/2 Inhibitor Pimasertib Enhances Gemcitabine Efficacy in Pancreatic Cancer Models by Altering Ribonucleotide Reductase Subunit-1 (RRM1)

“…Inhibitors of MEK protein have been developed to target this pathway but have shown limited efficacy when used in monotherapy in many tumors where they have been tested (42). Pimasertib (AS703026 or MSC1936369B) is a potent allosteric MEK1 and MEK2 inhibitor; in vitro and in vivo effects of pimasertib alone or in combination have been evaluated in several human cancers where MAPK pathway is commonly deregulated and have shown potent antitumor activity (22,23). In this study, we found that one mechanism by which pimasertib modulates gemcitabine activity is through a reduction in RRM1 protein expression, an important biomarker for gemcitabine resistance both in PDAC and NSCLC (16,27).…”

“…Pimasertib (MSC1936369B/AS703026) is a highly selective, small-molecule inhibitor of the protein kinase MEK1 and MEK2 and binds an allosteric site adjacent to the ATP binding site of MEK. Preclinical studies showed that pimasertib induced significant antitumor activity in xenograft models of mutant KRAS colorectal cancer (22). Furthermore, pimasertib treatment induced cell death in multiple myeloma cell lines, patient cells, and xenograft models and enhanced the cytotoxic effect of conventional anti-multiple myeloma therapies (23).…”