Nanomedicines blocking adaptive signals in cancer cells overcome tumor TKI resistance

Hiroaki Kinoh; Hitoshi Shibasaki; Xueying Liu; Tatsuya Yamasoba; Horacio Cabral; Kazunori Kataoka

doi:10.1016/j.jconrel.2020.02.008

Nanomedicines blocking adaptive signals in cancer cells overcome tumor TKI resistance

J Control Release. 2020 May 10:321:132-144. doi: 10.1016/j.jconrel.2020.02.008. Epub 2020 Feb 4.

Authors

Hiroaki Kinoh¹, Hitoshi Shibasaki², Xueying Liu¹, Tatsuya Yamasoba³, Horacio Cabral⁴, Kazunori Kataoka⁵

Affiliations

¹ Innovation Center of NanoMedicine, Kawasaki Institute of Industrial Promotion, 3-25-14, Tonomachi, Kawasaki-ku, Kawasaki 210-0821, Japan.
² Innovation Center of NanoMedicine, Kawasaki Institute of Industrial Promotion, 3-25-14, Tonomachi, Kawasaki-ku, Kawasaki 210-0821, Japan; Department of Otolaryngology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
³ Department of Otolaryngology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
⁴ Department of Bioengineering, Graduate School of Engineering, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8656, Japan. Electronic address: horacio@bmw.t.u-tokyo.ac.jp.
⁵ Innovation Center of NanoMedicine, Kawasaki Institute of Industrial Promotion, 3-25-14, Tonomachi, Kawasaki-ku, Kawasaki 210-0821, Japan; Institute for Future Initiatives, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan. Electronic address: kataoka@ifi.u-tokyo.ac.jp.

PMID: 32032656
DOI: 10.1016/j.jconrel.2020.02.008

Abstract

Tumor resistance to tyrosine kinase inhibitors (TKIs) is an inexorable clinical event. The manipulation of adaptive changes in cancer cells while inhibiting the signaling pathways could be an effective strategy for overcoming TKI resistance toward reducing tumor relapse and prolonging survival. Here, we tested this approach by using polymeric nanomedicines delivering the pan-kinase inhibitor staurosporine (STS) to treat renal cell carcinoma (RCC) resistant to the multi-targeted TKI sunitinib. STS blocked the activity of TKI-resistant protein kinases and strongly inhibited adaptive dynamics in RCC cells promoted by MDR1 and GLUT1 to overcome sunitinib resistance. Co-delivery of STS and epirubicin directed to eliminate fast-proliferating cancer cells through the same nanomedicine platform enabled safe and potent in vivo efficacy in mouse models of RCC, overcoming sunitinib resistance and suppressing the development of metastasis. These results indicate our approach as a promising strategy for effectively managing TKI resistance.

Keywords: Epirubicin; GLUT1; MDR1; Polymeric micelles; Renal cancer; Staurosporine; Sunitinib resistance.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Carcinoma, Renal Cell*
Cell Line, Tumor
Drug Resistance, Neoplasm
Kidney Neoplasms*
Mice
Nanomedicine
Protein Kinase Inhibitors / pharmacology

Substances

Protein Kinase Inhibitors