Combination of EGFR and MEK1/2 inhibitor shows synergistic effects by suppressing EGFR/HER3-dependent AKT activation in human gastric cancer cells

Abstract

EGFR tyrosine kinase inhibitors have shown promising efficacy in the treatment of tumors with EGFR mutations and amplifications. However, tyrosine kinase inhibitors have also proven ineffective against most tumors with EGFR wild-type (WT) alleles. Although some genetic changes, including the KRAS mutation, have been shown to confer resistance to tyrosine kinase inhibitors, novel strategies for the treatment of cancer patients with tumors harboring EGFR WT alleles have yet to be thoroughly delineated. The principal objective of this study was to improve our current understanding of drug interactions between EGFR and MAP/ERK kinase (MEK) inhibitors in an effort to gain insight into a novel therapeutic strategy against EGFR WT tumors. Using a panel of human EGFR WT gastric cancer cell lines, we showed that gastric cancer cells harboring the KRAS mutation were selectively sensitive to MEK inhibition as compared with those cells harboring KRAS and PI3K mutations and KRAS WT alleles. However, all cell lines were found to be resistant to EGFR inhibition. The results from Western blots and phosphoprotein arrays showed that, in MEK inhibitor resistant cell lines, AKT was activated through the EGFR/HER3/PI3K pathway following AZD6244 (ARRY-142886) treatment. Blockade of this feedback mechanism through the targeting of MEK and EGFR resulted in detectable synergistic effects in some cell lines in vitro and in vivo. Our results provide the basis for a rational combination strategy against human EGFR WT gastric cancers, predicated on the understanding of cross-talk between the MEK and EGFR pathways. [Mol Cancer Ther 2009;8(9):2526-36]

Antitumor Activity of Saracatinib (AZD0530), a c-Src/Abl Kinase Inhibitor, Alone or in Combination with Chemotherapeutic Agents in Gastric Cancer

“…The molecular alteration of these cells was previously reported (19). SNU216 and NCI-N87 cells were sensitive to saracatinib at IC 50 values lower than 1 mmol/L ( Table 1).…”

NO donor and MEK inhibitor synergistically inhibit proliferation and invasion of cancer cells

“…1 and 2). These results are in accordance with previous reports (43,44). Furthermore, we showed that U0126 upregulates IGF-Iand EGF-stimulated phosphorylation of IGF-IR and EGFR.…”

Evaluation of the Antitumor Effects and Mechanisms of PF00299804, a Pan-HER Inhibitor, Alone or in Combination with Chemotherapy or Targeted Agents in Gastric Cancer

“…The MEK inhibitor has been found to exert efficacy against KRASmutant cancer cell lines that are resistant to gefitinib. A combination of MEK and EGFR inhibitors showed synergistic effects via inhibition of the EGFR/HER3/AKT pathway activated in MEK inhibitor-resistant cells (34). Moreover, the combination of RAD001 plus trastuzumab was more effective than either drug alone, suggesting inhibition of PI3K and mTOR is required for the growth-inhibitory effect of HER2 antagonists (50).…”

“…The growth-inhibitory effects of PF00299804 in a panel of 11 gastric cancer cell lines (SNU-1, 5, 16, 216, 484, 601, 620, 638, 668, 719, and N87), of which genetic status was previously reported, were examined (34). Interestingly, only HER2-amplified gastric cancer cells (SNU216 and N87) were sensitive to PF00299804 with a low range of IC 50 values (0.002-0.008 mmol/L).…”