Dual inhibition of MEK1/2 and EGFR synergistically induces caspase-3-dependent apoptosis in EGFR inhibitor-resistant lung cancer cells via BIM upregulation.

Abstract

Epidermal growth factor receptor (EGFR) gene mutations activate the KRAS-RAF-MEK-ERK pathway in lung cancer cells. EGFR tyrosine kinase inhibitors (TKIs) such as gefitinib induce apoptosis of cancer cells, but prolonged treatment is often associated with acquired resistance. Here, we identified a novel MEK1/2 inhibitor, CZ0775, and compared its cytotoxic effects to those of AZD6244 (selumetinib) in non-small cell lung cancer (NSCLC) cell lines harboring EGFR mutations. The lapatinib-sensitive HCC827 and PC9 and lapatinib-resistant H1650 and H1975 cell lines showed poor responses to CZ0775 and AZD6244 monotherapy with an IC50 > 10 μM. By contrast, combination treatment with lapatinib and CZ0775 inhibited cell proliferation and produced a 2-fold higher number of annexin V-labeled cells than lapatinib alone in H1975 cells. Furthermore, combination treatment decreased phosphorylated extracellular signal related kinase (p-ERK) and survivin levels and upregulated the expression of the pro-apoptotic protein BIM. siRNA-mediated BIM depletion reduced caspase-3 activity (~40%) in lapatinib and CZ0775 treated H1975 cells. An in vitro ERK activity assay showed that p-ERK levels were approximately a 3-fold lower in H1975 cells treated with CZ0775 and lapatinib combination than in cells treated with lapatinib alone. CZ0775 was more cytotoxic than AZD6244 when used in combination with lapatinib. Our results suggest that combination treatment with CZ0774 and EGFR inhibitors is a promising therapeutic approach for the treatment of EGFR-TKI-resistant lung cancers and its effect is mediated by the inhibition of ERK and the induction of BIM.

• Authors: Ji-Young Song, Choung-Soo Kim, Je-Hwan Lee, Se Jin Jang, Sang-wook Lee, Jung Jin Hwang, Chulsoo Lim, Gilnam Lee, Jeongbeob Seo, Suk Young Cho, Jene Choi
• Journal: Investigational new drugs (Invest New Drugs) Vol. 31 Issue 6 Pg. 1458-65 (Dec 2013) ISSN: 1573-0646 [Electronic] United States
• PMID: 24068620 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• AZD 6244
• Antineoplastic Agents
• Apoptosis Regulatory Proteins
• BCL2L11 protein, human
• Bcl-2-Like Protein 11
• Benzimidazoles
• CZ0775
• Membrane Proteins
• Protein Kinase Inhibitors
• Proto-Oncogene Proteins
• Pyridones
• Quinazolines
• Sulfonamides
• Lapatinib
• MAP2K2 protein, human
• ErbB Receptors
• MAP Kinase Kinase 1
• MAP Kinase Kinase 2
• MAP2K1 protein, human
• Caspase 3
• Gefitinib

Topics

• Antineoplastic Agents (administration & dosage)
• Apoptosis
• Apoptosis Regulatory Proteins (metabolism)
• Bcl-2-Like Protein 11
• Benzimidazoles (administration & dosage)
• Carcinoma, Non-Small-Cell Lung (drug therapy, metabolism)
• Caspase 3 (metabolism)
• Cell Line, Tumor
• Drug Synergism
• ErbB Receptors (antagonists & inhibitors, genetics)
• Gefitinib
• Humans
• Lapatinib
• Lung Neoplasms (drug therapy, metabolism)
• MAP Kinase Kinase 1 (antagonists & inhibitors)
• MAP Kinase Kinase 2 (antagonists & inhibitors)
• Membrane Proteins (metabolism)
• Mutation
• Protein Kinase Inhibitors (administration & dosage)
• Proto-Oncogene Proteins (metabolism)
• Pyridones (administration & dosage)
• Quinazolines (administration & dosage)
• Sulfonamides (administration & dosage)