FS-93, an Hsp90 inhibitor, induces G2/M arrest and apoptosis via the degradation of client proteins in oncogene addicted and derived resistant cancer cells
Liping Zhang3,*, Aijun Shen1,*, Lu Wang1, Hongchun Liu1, Danqi Chen2, Bing Xiong2, Jingkang Shen2 and Meiyu Geng1
1 Division of Anti-tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China
2 Synthetic Organic and Medicinal Chemistry Laboratory, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China
3 School of Medicine and Pharmacy, Ocean University of China, Shandong, China
* These authors have contributed equally to this work
Correspondence:
Meiyu Geng, email:
Keywords: hsp90, oncogene addiction, resistance, G2/M arrest, apoptosis
Received: March 06, 2015 Accepted: April 08, 2015 Published: April 22, 2015
Abstract
Inhibition of heat shock protein 90 (Hsp90) abrogates signaling of multiple aberrantly activated oncogenic proteins simultaneously, particularly mutated or amplified kinases, which provides an attractive approach for cancer treatment. Here, we described that FS-93, a potent Hsp90 inhibitor, impacted the survival of several types of oncogene addicted cancer cells through inducing G2/M arrest and apoptosis. Mechanistically, FS-93 treatment triggered the degradation of key client proteins such as HER2, EML4-ALK and c-Met and thereby abolished their downstream signaling pathways. Importantly, FS-93 alone circumvented MET amplification contributed acquired resistance to EGFR inhibition. Our study implicates that targeting Hsp90 is a promising alternative therapeutic tactic in oncogene addicted and derived resistant cancer cells.
