EPHA2 Blockade Overcomes Acquired Resistance to EGFR Kinase Inhibitors in Lung Cancer.

Abstract

Despite the success of treating EGFR-mutant lung cancer patients with EGFR tyrosine kinase inhibitors (TKI), all patients eventually acquire resistance to these therapies. Although various resistance mechanisms have been described, there are currently no FDA-approved therapies that target alternative mechanisms to treat lung tumors with acquired resistance to first-line EGFR TKI agents. Here we found that EPHA2 is overexpressed in EGFR TKI-resistant tumor cells. Loss of EPHA2 reduced the viability of erlotinib-resistant tumor cells harboring EGFR(T790M) mutations in vitro and inhibited tumor growth and progression in an inducible EGFR(L858R+T790M)-mutant lung cancer model in vivo. Targeting EPHA2 in erlotinib-resistant cells decreased S6K1-mediated phosphorylation of cell death agonist BAD, resulting in reduced tumor cell proliferation and increased apoptosis. Furthermore, pharmacologic inhibition of EPHA2 by the small-molecule inhibitor ALW-II-41-27 decreased both survival and proliferation of erlotinib-resistant tumor cells and inhibited tumor growth in vivo. ALW-II-41-27 was also effective in decreasing viability of cells with acquired resistance to the third-generation EGFR TKI AZD9291. Collectively, these data define a role for EPHA2 in the maintenance of cell survival of TKI-resistant, EGFR-mutant lung cancer and indicate that EPHA2 may serve as a useful therapeutic target in TKI-resistant tumors.

• Authors: Katherine R Amato, Shan Wang, Li Tan, Andrew K Hastings, Wenqiang Song, Christine M Lovly, Catherine B Meador, Fei Ye, Pengcheng Lu, Justin M Balko, Daniel C Colvin, Justin M Cates, William Pao, Nathanael S Gray, Jin Chen
• Journal: Cancer research (Cancer Res) Vol. 76 Issue 2 Pg. 305-18 (Jan 15 2016) ISSN: 1538-7445 [Electronic] United States
• PMID: 26744526 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: ©2016 American Association for Cancer Research.

Chemical References

• ALW-II-41-27
• Benzamides
• Protein Kinase Inhibitors
• Niacinamide
• Erlotinib Hydrochloride
• EGFR protein, human
• ErbB Receptors
• Receptor, EphA2

Topics

• Animals
• Antineoplastic Combined Chemotherapy Protocols (pharmacology)
• Apoptosis (drug effects)
• Benzamides (administration & dosage, pharmacology)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Drug Resistance, Neoplasm
• Drug Synergism
• ErbB Receptors (administration & dosage, antagonists & inhibitors, metabolism)
• Erlotinib Hydrochloride (administration & dosage, pharmacology)
• Humans
• Lung Neoplasms (drug therapy, enzymology, genetics, pathology)
• Mice
• Mice, Nude
• Niacinamide (administration & dosage, analogs & derivatives, pharmacology)
• Protein Kinase Inhibitors (pharmacology)
• Receptor, EphA2 (antagonists & inhibitors, genetics, metabolism)
• Signal Transduction
• Xenograft Model Antitumor Assays