4.8 Article

Nanomedicines blocking adaptive signals in cancer cells overcome tumor TKI resistance

Journal

JOURNAL OF CONTROLLED RELEASE
Volume 321, Issue -, Pages 132-144

Publisher

ELSEVIER
DOI: 10.1016/j.jconrel.2020.02.008

Keywords

Polymeric micelles; Renal cancer; Sunitinib resistance; MDR1; GLUT1; Epirubicin; Staurosporine

Funding

  1. Center of Innovation Program (COI stream) from the Japan Science and Technology Agency (JST) from the Japan Society for the Promotion of Science (JSPS) [JPMJCE1305]
  2. Project for Cancer Research and Therapeutic Evolution (P-CREATE) from the Japan Agency for Medical Research and Development (AMED) [16cm0106202h0001]
  3. Japan Society for the Promotion of Science (JSPS) [JP18H04170, JP16H03179]

Ask authors/readers for more resources

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.

Authors

I am an author on this paper
Click your name to claim this paper and add it to your profile.

Reviews

Primary Rating

4.8
Not enough ratings

Secondary Ratings

Novelty
-
Significance
-
Scientific rigor
-
Rate this paper

Recommended

No Data Available
No Data Available