Dual MET-EGFR combinatorial inhibition against T790M-EGFR-mediated erlotinib-resistant lung cancer.

Abstract

Despite clinical approval of erlotinib, most advanced lung cancer patients are primary non-responders. Initial responders invariably develop secondary resistance, which can be accounted for by T790M-EGFR mutation in half of the relapses. We show that MET is highly expressed in lung cancer, often concomitantly with epidermal growth factor receptor (EGFR), including H1975 cell line. The erlotinib-resistant lung cancer cell line H1975, which expresses L858R/T790M-EGFR in-cis, was used to test for the effect of MET inhibition using the small molecule inhibitor SU11274. H1975 cells express wild-type MET, without genomic amplification (CNV = 1.1). At 2 microM, SU 11274 had significant in vitro pro-apoptotic effect in H1975 cells, 3.9-fold (P = 0.0015) higher than erlotinib, but had no effect on the MET and EGFR-negative H520 cells. In vivo, SU11274 also induced significant tumour cytoreduction in H1975 murine xenografts in our bioluminescence molecular imaging assay. Using small-animal microPET/MRI, SU11274 treatment was found to induce an early tumour metabolic response in H1975 tumour xenografts. MET and EGFR pathways were found to exhibit collaborative signalling with receptor cross-activation, which had different patterns between wild type (A549) and L858R/T790M-EGFR (H1975). SU11274 plus erlotinib/CL-387,785 potentiated MET inhibition of downstream cell proliferative survival signalling. Knockdown studies in H1975 cells using siRNA against MET alone, EGFR alone, or both, confirmed the enhanced downstream inhibition with dual MET-EGFR signal path inhibition. Finally, in our time-lapse video-microscopy and in vivo multimodal molecular imaging studies, dual SU11274-erlotinib concurrent treatment effectively inhibited H1975 cells with enhanced abrogation of cytoskeletal functions and complete regression of the xenograft growth. Together, our results suggest that MET-based targeted inhibition using small-molecule MET inhibitor can be a potential treatment strategy for T790M-EGFR-mediated erlotinib-resistant non-small-cell lung cancer. Furthermore, optimised inhibition may be further achieved with MET inhibition in combination with erlotinib or an irreversible EGFR-TKI.

• Authors: Z Tang, R Du, S Jiang, C Wu, D S Barkauskas, J Richey, J Molter, M Lam, C Flask, S Gerson, A Dowlati, L Liu, Z Lee, B Halmos, Y Wang, J A Kern, P C Ma
• Journal: British journal of cancer (Br J Cancer) Vol. 99 Issue 6 Pg. 911-22 (Sep 16 2008) ISSN: 0007-0920 [Print] England
• PMID: 19238632 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• ((3Z)-N-(3-chlorophenyl)-3-((3,5-dimethyl-4-((4-methylpiperazin-1-yl)carbonyl)-1H-pyrrol-2-yl)methylene)-N-methyl-2-oxo-2,3-dihydro-1H-indole-5-sulfonamide)
• Indoles
• Piperazines
• Proto-Oncogene Proteins
• Quinazolines
• RNA, Small Interfering
• Receptors, Growth Factor
• Sulfonamides
• Erlotinib Hydrochloride
• Luciferases
• EGFR protein, human
• ErbB Receptors
• MET protein, human
• Proto-Oncogene Proteins c-met

Topics

• Animals
• Drug Resistance, Neoplasm
• Drug Therapy, Combination
• ErbB Receptors (antagonists & inhibitors, metabolism)
• Erlotinib Hydrochloride
• Humans
• Immunoblotting
• Immunoprecipitation
• Indoles (therapeutic use)
• Luciferases (metabolism)
• Lung Neoplasms (drug therapy, metabolism, pathology)
• Magnetic Resonance Imaging
• Mice
• Mice, Nude
• Piperazines (therapeutic use)
• Positron-Emission Tomography
• Proto-Oncogene Proteins (antagonists & inhibitors, metabolism)
• Proto-Oncogene Proteins c-met
• Quinazolines (therapeutic use)
• RNA, Small Interfering (pharmacology)
• Receptors, Growth Factor (antagonists & inhibitors, metabolism)
• Sulfonamides (therapeutic use)
• Xenograft Model Antitumor Assays