期刊
FASEB JOURNAL
卷 33, 期 1, 页码 1347-1359出版社
FEDERATION AMER SOC EXP BIOL
DOI: 10.1096/fj.201800596R
关键词
kidney cancer; differential drug response; receptor tyrosine kinase inhibitor
资金
- Animal Care Committee of the Keenan Research Centre
- Canadian Institutes of Health Research [MOP-119606]
- Kidney Foundation of Canada [KFOC130030]
- Prostate Cancer Canada Movember Discovery Grants [D2013-39]
- Kidney Research Scientist Core Education
- National Training Program Postdoctoral Award from the Kidney Foundation of Canada
Sunitinib is the standard-of-care, first-line treatment for advanced renal cell carcinoma (RCC). Characteristics of treatment-resistant RCC have been described; however, complex tumor adaptation mechanisms obstruct the identification of significant operators in resistance. We hypothesized that resistance is a late manifestation of early, treatment-induced histomolecular alterations; therefore, studying early drug response may identify drivers of resistance. We describe an epithelioid RCC growth pattern in RCC xenografts, which emerges in sunitinib-sensitive tumors and is augmented during resistance. This growth modality is molecularly and morphologically related to the RCC spheroids that advance during in vitro treatment. Based on time-lapse microscopy, mRNA and microRNA screening, and tumor behavior-related characteristics, we propose that the spheroid and adherent RCC growth patterns differentially respond to sunitinib. Gene expression analysis indicated that sunitinib promoted spheroid formation, which provided a selective survival advantage under treatment. Functional studies confirm that E-cadherin is a key contributor to the survival of RCC cells under sunitinib treatment. In summary, we suggest that sunitinib-resistant RCC cells exist in treatment-sensitive tumors and are histologically identifiable.Lichner, Z., Saleeb, R., Butz, H., Ding, Q., Nofech-Mozes, R., Riad, S., Farag, M., Varkouhi, A. K., dos Santos, C. C., Kapus, A., Yousef, G. M. Sunitinib induces early histomolecular changes in a subset of renal cancer cells that contribute to resistance.
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