Sunitinib is considered a first-line therapeutic option for patients with advanced clear cell renal cell carcinoma (ccRCC).
Despite sunitinib's clinical efficacy, patients eventually develop drug resistance and disease progression. Herein, we tested the hypothesis whether initial sunitinib resistance may be transient and could be overcome by dose increase. In selected patients initially treated with 50 mg sunitinib and presenting with minimal toxicities, sunitinib dose was escalated to 62.5 mg and/or 75 mg at the time of tumor progression. Mice bearing two different patient-derived ccRCC xenografts (PDX) were treated 5 days per week with a dose-escalation schema (40-60-80 mg/kg sunitinib). Tumor tissues were collected before dose increments for immunohistochemistry analyses and drug levels. Selected intrapatient sunitinib dose escalation was safe and several patients had added progression-free survival. In parallel, our preclinical results showed that PDXs, although initially responsive to sunitinib at 40 mg/kg, eventually developed resistance. When the dose was incrementally increased, again we observed tumor response to sunitinib. A resistant phenotype was associated with transient increase of tumor vasculature despite intratumor sunitinib accumulation at higher dose. In addition, we observed associated changes in the expression of the methyltransferase EZH2 and histone marks at the time of resistance. Furthermore, specific EZH2 inhibition resulted in increased in vitro antitumor effect of sunitinib. Overall, our results suggest that initial sunitinib-induced resistance may be overcome, in part, by increasing the dose, and highlight the potential role of epigenetic changes associated with sunitinib resistance that can represent new targets for therapeutic intervention.
Written by:
Adelaiye R, Ciamporcero E, Miles KM, Sotomayor P, Bard J, Tsompana M, Conroy D, Shen L, Ramakrishnan S, Ku SY, Orillion A, Prey J, Fetterly G, Buck M5, Chintala S, Bjarnason GA, Pili R. Are you the author?
Genitourinary Program, Roswell Park Cancer Institute, Buffalo, New York; Department of Cancer Pathology and Prevention, Roswell Park Cancer Institute Division, University at Buffalo, Buffalo, New York; Department of Medicine and Experimental Oncology, University of Turin, Turin, Italy; Center of Excellence in Bioinformatics and Life Sciences, University at Buffalo, Buffalo, New York; Department of Molecular and Cellular Biology, Roswell Park Cancer Institute, Buffalo, New York; Pharmacokinetics and Pharmacodynamics Core Facility, Roswell Park Cancer Institute, Buffalo, New York; Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Buffalo, New York; Sunnybrook Odette Cancer Center, University of Toronto, Toronto, Ontario, Canada.
Reference: Mol Cancer Ther. 2015 Feb;14(2):513-22.
doi: 10.1158/1535-7163.MCT-14-0208
PubMed Abstract
PMID: 25519701