Heat‐shock protein 27 (HSP27, HSPB1) is up‐regulated by MET kinase inhibitors and confers resistance to MET‐targeted therapy. Issue 9 (5th June 2014)

• Record Type: Journal Article
• Authors: Musiani, Daniele; Konda, John David; Pavan, Simona; Torchiaro, Erica; Sassi, Francesco; Noghero, Alessio; Erriquez, Jessica; Perera, Timothy; Olivero, Martina; Di Renzo, Maria Flavia
• Is Part Of: FASEB journal. Volume 28:Issue 9(2014)
• Page Start: 4055
• Page End: 4067
• Publication Date: 2014-06-05
• Subjects: hepatocyte growth factor receptor -- EGFR; Biology -- Periodicals; Biology, Experimental -- Periodicals; 570
• DOI: 10.1096/fj.13-247924
• Languages: English
• ISSNs: 0892-6638

Abstract

Abstract : The tyrosine kinase encoded by the MET oncogene is activated by gene mutation or amplification in tumors, which in most instances maintain addiction, i.e., dependency, to MET activation. This makes MET an attractive candidate for targeted therapies. Here we show that, in 3/3 MET‐addicted human gastric cancer cell lines, MET kinase inhibition resulted in a 3‐ to 4‐fold increased expression of the antiapoptotic small heat‐shock protein of 27 kDa (HSP27, HSPB1). HSP27 increase depended on the inhibition of the MEK/ERK pathway and on heat‐shock factor 1 (HSF1) and hypoxia‐inducible factor‐1α (HIF‐1α) regulation. Importantly, HSP27‐silenced MET‐addicted cells underwent 2‐ and 3‐fold more apoptosis following MET inhibition in vitro and in vivo, respectively. Likewise, in human cancer cells susceptible to epidermal growth factor receptor (EGFR) inhibition, EGFR inhibitors induced HSP27 expression and were strengthened by HSP27 suppression. In control cell lines that were not affected by drugs targeting MET or EGFR, these drugs did not induce HSP27 increase. Therefore, in cancer therapies targeting the MET pathway, the induction of HSP27 might limit the efficacy of anti‐MET agents. As HSP27 increase also impairs the effectiveness of EGFR inhibitors and is known to protect cells from chemotherapeutics, the induction of HSP27 by targeted agents might strongly affect the success of combination treatments.—Musiani, D., Konda, J. D., Pavan, S., Torchiaro, E., Sassi, F., Noghero, A., Erriquez, J., Perera, T., Olivero, M., Di Renzo, M. F. Heat‐shock protein 27 (HSP27, HSPB1) is up‐regulated by MET kinase inhibitors and confers resistance to MET‐targeted therapy. FASEB J. 28, 4055‐4067 (2014). www.fasebj.org