Antitumor activity of selective MEK1/2 inhibitor AZD6244 in combination with PI3K/mTOR inhibitor BEZ235 in gefitinib-resistant NSCLC xenograft models.

Abstract

PURPOSE:

Although the EGF receptor tyrosine kinase inhibitors (EGFR-TKI) gefitinib have shown dramatic effects against EGFR mutant lung cancer, patients become resistant by various mechanisms, including gatekeeper EGFR-T790M mutation, MET amplification, and KRAS mutation, thereafter relapsing. AZD6244 is a potent, selective, and orally available MEK1/2 inhibitor. In this study, we evaluated the therapeutic efficacy of AZD6244 alone or with BEZ235, an orally available potent inhibitor of phosphatidylinositol 3-kinase (PI3K) and mammalian target of rapamycin (mTOR), in gefitinib-resistant non-small cell lung carcinoma (NSCLC) models.

EXPERIMENTAL DESIGN:

NCI-H1975 with EGFR-T790M mutation, NCI-H1993 with MET amplification and NCI-H460 with KRAS/PIK3CA mutation human NSCLC cells were subcutaneous injected into the athymic nude mice respectively. Mice were randomly assigned to treatment with AZD6244, BEZ235, AZD6244 plus BEZ235, or control for 3 weeks, then all mice were sacrificed and tumor tissues were subjected to western blot analyses and immunohistochemical staining.

RESULTS:

AZD6244 could inhibit the tumor growth of NCI-H1993, but slightly inhibit the tumor growth of NCI-1975 and NCI-H460. Combining AZD6244 with BEZ235 markedly enhanced their antitumor effects and without any marked adverse events. Western blot analysis and immunohistochemical staining revealed that AZD6244 alone reduced ERK1/2 phosphorylation, angiogenesis, and tumor cell proliferation. Moreover, MEK1/2 inhibition resulted in decreased AKT phosphorylation in NCI-H1993 tumor model. BEZ235 also inhibited AKT phosphorylation as well as their downstream molecules in all three tumor models. The antiangiogenic effects were substantially enhanced when the agents were combined, which may due to the reduced expression of matrix metallopeptidase-9 in tumor tissues (MMP-9).

CONCLUSIONS:

In this study, we evaluated therapy directed against MEK and PI3K/mTOR in distinct gefitinib-resistant NSCLC xenograft models. Combining AZD6244 with BEZ235 enhanced their antitumor and antiangiogenic effects. We concluded that the combination of a selective MEK inhibitor and a PI3K/mTOR inhibitor was effective in suppressing the growth of gefitinib-resistant tumors caused by EGFR T790M mutation, MET amplification, and KRAS/PIK3CA mutation. This new therapeutic strategy may be a practical approach in the treatment of these patients.

• Authors: Yiqing Qu, Xiuxiu Wu, Yunhong Yin, Yan Yang, Dedong Ma, Hao Li
• Journal: Journal of experimental & clinical cancer research : CR (J Exp Clin Cancer Res) Vol. 33 Pg. 52 (Jun 17 2014) ISSN: 1756-9966 [Electronic] England
• PMID: 24939055 (Publication Type: Journal Article)

Chemical References

• AZD 6244
• Benzimidazoles
• Imidazoles
• Ki-67 Antigen
• Phosphoinositide-3 Kinase Inhibitors
• Platelet Endothelial Cell Adhesion Molecule-1
• Protein Kinase Inhibitors
• Quinazolines
• Quinolines
• Protein Kinases
• Caspases
• dactolisib
• Gefitinib

Topics

• Animals
• Benzimidazoles (pharmacology)
• Carcinoma, Non-Small-Cell Lung (drug therapy, enzymology, pathology)
• Caspases (metabolism)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cell Survival (drug effects)
• Drug Resistance, Neoplasm
• Drug Synergism
• Female
• Gefitinib
• Humans
• Imidazoles (pharmacology)
• Ki-67 Antigen (metabolism)
• Lung Neoplasms (drug therapy, enzymology, pathology)
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• Phosphatidylinositol 3-Kinases (metabolism)
• Phosphoinositide-3 Kinase Inhibitors
• Platelet Endothelial Cell Adhesion Molecule-1 (metabolism)
• Protein Kinase Inhibitors (pharmacology)
• Protein Kinases (metabolism)
• Quinazolines (pharmacology)
• Quinolines (pharmacology)
• Signal Transduction
• Tumor Burden (drug effects)
• Xenograft Model Antitumor Assays