Synergistic effect between erlotinib and MEK inhibitors in KRAS wild-type human pancreatic cancer cells.

Abstract

PURPOSE:

The combination of erlotinib and gemcitabine has shown a small but statistically significant survival advantage when compared with gemcitabine alone in patients with advanced pancreatic cancer. However, the overall survival rate with the erlotinib and gemcitabine combination is still low. In this study, we sought to identify gene targets that, when inhibited, would enhance the activity of epidermal growth factor receptor (EGFR)-targeted therapies in pancreatic cancer cells.

EXPERIMENTAL DESIGN:

A high-throughput RNA interference (RNAi) screen was carried out to identify candidate genes. Selected gene hits were further confirmed and mechanisms of action were further investigated using various assays.

RESULTS:

Six gene hits from siRNA screening were confirmed to significantly sensitize BxPC-3 pancreatic cancer cells to erlotinib. One of the hits, mitogen-activated protein kinase (MAPK) 1, was selected for further mechanistic studies. Combination treatments of erlotinib and two MAP kinase kinase (MEK) inhibitors, RDEA119 and AZD6244, showed significant synergistic effect for both combinations (RDEA119-erlotinib and AZD6244-erlotinib) compared with the corresponding single drug treatments in pancreatic cancer cell lines with wild-type KRAS (BxPC-3 and Hs 700T) but not in cell lines with mutant KRAS (MIA PaCa-2 and PANC-1). The enhanced antitumor activity of the combination treatment was further verified in the BxPC-3 and MIA PaCa-2 mouse xenograft model. Examination of the MAPK signaling pathway by Western blotting indicated effective inhibition of the EGFR signaling by the drug combination in KRAS wild-type cells but not in KRAS mutant cells.

CONCLUSIONS:

Overall, our results suggest that combination therapy of an EGFR and MEK inhibitors may have enhanced efficacy in patients with pancreatic cancer.

• Authors: Caroline H Diep, Ruben M Munoz, Ashish Choudhary, Daniel D Von Hoff, Haiyong Han
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 17 Issue 9 Pg. 2744-56 (May 01 2011) ISSN: 1557-3265 [Electronic] United States
• PMID: 21385921 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: ©2011 AACR.

Chemical References

• KRAS protein, human
• Protein Kinase Inhibitors
• Proto-Oncogene Proteins
• Quinazolines
• Erlotinib Hydrochloride
• MAP Kinase Kinase Kinases
• Proto-Oncogene Proteins p21(ras)
• ras Proteins

Topics

• Animals
• Carcinoma, Pancreatic Ductal (drug therapy, genetics, pathology)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Drug Synergism
• Erlotinib Hydrochloride
• Female
• Humans
• MAP Kinase Kinase Kinases (antagonists & inhibitors)
• Mice
• Mice, Inbred ICR
• Mice, SCID
• Mice, Transgenic
• Mutation (physiology)
• Pancreatic Neoplasms (drug therapy, genetics, pathology)
• Protein Kinase Inhibitors (administration & dosage, pharmacology)
• Proto-Oncogene Proteins (genetics, metabolism)
• Proto-Oncogene Proteins p21(ras)
• Quinazolines (administration & dosage, pharmacology)
• Xenograft Model Antitumor Assays
• ras Proteins (genetics, metabolism)