Couple of papers regarding the non-MET mechanism by which tivantinib also operates:
>>Off-Target Effects of c-MET Inhibitors on Thyroid Cancer Cells
Yan Zhou 1, 2, 4, Conghui Zhao 1, Sigal Gery 4, Glenn D. Braunstein 4, Ryoko Okamoto 4, Rocio Alvarez 4, Steven A. Miles 4, Ngan B. Doan 5, Jonathan W. Said 5, Jiang Gu 1, 3, and H. Phillip Koeffler 4, 6 + Author Affiliations
Authors' Affiliations: 1Department of Pathology, School of Basic Medical Sciences, Peking University; 2Novogene Bioinformatics Institute, Beijing; 3Shantou University Medical College, Shantou, China; 4Department of Medicine, Cedars-Sinai Medical Center, UCLA School of Medicine; 5Department of Pathology, UCLA Medical Center, Los Angeles, California; and 6Cancer Science Institute and National Cancer Institute, National University of Singapore, Singapore Corresponding Authors:
Yan Zhou, Department of Pathology, School of Basic Medical Sciences, Peking (Beijing) University, Beijing, China. Phone: 86-10-82802998; Fax: 86-10-82802998; E-mail: zzz2008yyy@gmail.com; and Jiang Gu, jguemailbox@gmail.com Y. Zhou and C. Zhao contributed equally to this work.
Abstract Aberrantly activated c-MET signaling occurs in several cancers, promoting the development of c-MET inhibitors. In this study, we found that eight of eight thyroid cancer cell lines (including six anaplastic thyroid cell lines) have prominent expression of c-MET protein. Fifty percent of the thyroid cancer cell lines (four of eight) were growth inhibited by two small molecule c-MET inhibitors (tivantinib and crizotinib) associated with apoptosis and G2–M cell-cycle arrest. However, crizotinib did not inhibit 50% proliferation of thyroid cancer cells (SW1736 and TL3) at a concentration at which the drug completely inhibited ligand-stimulated c-MET phosphorylation. However, tivantinib was less potent than crizotinib at inhibiting c-MET phosphorylation, but was more potent than crizotinib at decreasing cell growth. Suppressing c-MET protein expression and phosphorylation using siRNA targeting c-MET did not induce cell-cycle arrest and apoptosis. Taken together, tivantinib and crizotinib have off-target(s) activity, contributing to their antitumor activity. In vivo study showed that crizotinib markedly inhibited the growth of thyroid cancer cells (SW1736) in immunodeficient mice. In summary, c-MET inhibitors (tivantinib and crizotinib) suppress the growth of aggressive thyroid cancer cells, and this potential therapeutic benefit results from their non–MET-targeting effects. Mol Cancer Ther; 13(1); 134–43. ©2013 AACR.<<
And this one from last year (hat tip to tony111 on IHub for the dig.
>>Cytotoxic Activity of Tivantinib (ARQ 197) Is Not Due Solely to c-MET Inhibition
Ryohei Katayama 1, 2, 3, Aki Aoyama 3, 5, Takao Yamori 4, 6, Jie Qi 1, Tomoko Oh-hara 3, Youngchul Song 1, Jeffrey A. Engelman 1, 2, and Naoya Fujita 1, 3 + Author Affiliations
Authors' Affiliations: 1Massachusetts General Hospital Cancer Center; 2Department of Medicine, Harvard Medical School, Boston, Massachusetts; Divisions of 3Experimental Chemotherapy and 4Molecular Pharmacology, Cancer Chemotherapy Center, Japanese foundation for Cancer Research; 5Department of Medical Genome Sciences, Graduate School of Frontier Sciences, The University of Tokyo; and 6Pharmaceuticals and Medical Devices Agency (PMDA), Tokyo, Japan Corresponding Authors:
Jeffrey A. Engelman, Bldg149, 13th Street, Charlestown, MA 02129. Phone: 617-724-7298; Fax: 617-724-9648. E-mail: jengelman@partners.org; and Naoya Fujita, 3-8-31, Ariake, Koto-ku, Tokyo, 135-8550, Japan. Phone: 81-3-3570-0468; Fax: 81-3-3570-0484; E-mail: naoya.fujita@jfcr.or.jp R. Katayama and A. Aoyama contributed equally to this work.
Abstract The receptor tyrosine kinase c-MET is the high-affinity receptor for the hepatocyte growth factor (HGF). The HGF/c-MET axis is often dysregulated in tumors. c-MET activation can be caused by MET gene amplification, activating mutations, and auto- or paracrine mechanisms. Thus, c-MET inhibitors are under development as anticancer drugs. Tivantinib (ARQ 197) was reported as a small-molecule c-MET inhibitor and early clinical studies suggest antitumor activity. To assess whether the antitumor activity of tivantinib was due to inhibition of c-MET, we compared the activity of tivantinib with other c-MET inhibitors in both c-MET–addicted and nonaddicted cancer cells. As expected, other c-MET inhibitors, crizotinib and PHA-665752, suppressed the growth of c-MET-addicted cancers, but not the growth of cancers that are not addicted to c-MET. In contrast, tivantinib inhibited cell viability with similar potency in both c-MET-addicted and nonaddicted cells. These results suggest that tivantinib exhibits its antitumor activity in a manner independent of c-MET status. Tivantinib treatment induced a G2–M cell-cycle arrest in EBC1 cells similarly to vincristine treatment, whereas PHA-665752 or crizotinib treatment markedly induced G0–G1 cell-cycle arrest. To identify the additional molecular target of tivantinib, we conducted COMPARE analysis, an in silico screening of a database of drug sensitivities across 39 cancer cell lines (JFCR39), and identified microtubule as a target of tivantinib. Tivantinib-treated cells showed typical microtubule disruption similar to vincristine and inhibited microtubule assembly in vitro. These results suggest that tivantinib inhibits microtubule polymerization in addition to inhibiting c-MET. Cancer Res; 73(10); 3087–96. ©2013 AACR.<<
There was a response and a letter regarding this last one, but I don't have access to them. I know you saw at least this last, mcbio, but posting for posterity and discussion, particularly in the context of Peter's notions on whether or not CMet by itself is a good target.
Message 29409598
Watching, no position. Might take a small bet on a general market pullback. Market seems at the height of hubris now, more or less patting itself on the back for defusing the Ukraine situation.
Cheers, Tuck |
