title: Sunitinib dose escalation overcomes transient resistance in clear cell renal cell carcinoma and is associated with epigenetic modifications.
abstract: 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.
authors.affiliation: 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.
authors.forename: Remi
authors.initials: R
authors.lastname: Adelaiye
authors.affiliation: Genitourinary Program, Roswell Park Cancer Institute, Buffalo, New York. Department of Medicine and Experimental Oncology, University of Turin, Turin, Italy.
authors.forename: Eric
authors.initials: E
authors.lastname: Ciamporcero
authors.affiliation: Genitourinary Program, Roswell Park Cancer Institute, Buffalo, New York.
authors.forename: Kiersten Marie
authors.initials: KM
authors.lastname: Miles
authors.affiliation: Genitourinary Program, Roswell Park Cancer Institute, Buffalo, New York. Department of Molecular and Cellular Biology, Roswell Park Cancer Institute, Buffalo, New York.
authors.forename: Paula
authors.initials: P
authors.lastname: Sotomayor
authors.affiliation: Center of Excellence in Bioinformatics and Life Sciences, University at Buffalo, Buffalo, New York.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Bard
authors.affiliation: Center of Excellence in Bioinformatics and Life Sciences, University at Buffalo, Buffalo, New York.
authors.forename: Maria
authors.initials: M
authors.lastname: Tsompana
authors.affiliation: Genitourinary Program, Roswell Park Cancer Institute, Buffalo, New York.
authors.forename: Dylan
authors.initials: D
authors.lastname: Conroy
authors.affiliation: Genitourinary Program, Roswell Park Cancer Institute, Buffalo, New York.
authors.forename: Li
authors.initials: L
authors.lastname: Shen
authors.affiliation: 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.
authors.forename: Swathi
authors.initials: S
authors.lastname: Ramakrishnan
authors.affiliation: 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.
authors.forename: Sheng-Yu
authors.initials: SY
authors.lastname: Ku
authors.affiliation: Department of Molecular and Cellular Biology, Roswell Park Cancer Institute, Buffalo, New York.
authors.forename: Ashley
authors.initials: A
authors.lastname: Orillion
authors.affiliation: Pharmacokinetics and Pharmacodynamics Core Facility, Roswell Park Cancer Institute, Buffalo, New York.
authors.forename: Joshua
authors.initials: J
authors.lastname: Prey
authors.affiliation: Pharmacokinetics and Pharmacodynamics Core Facility, Roswell Park Cancer Institute, Buffalo, New York.
authors.forename: Gerald
authors.initials: G
authors.lastname: Fetterly
authors.affiliation: Center of Excellence in Bioinformatics and Life Sciences, University at Buffalo, Buffalo, New York.
authors.forename: Michael
authors.initials: M
authors.lastname: Buck
authors.affiliation: Genitourinary Program, Roswell Park Cancer Institute, Buffalo, New York. Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Buffalo, New York.
authors.forename: Sreenivasulu
authors.initials: S
authors.lastname: Chintala
authors.affiliation: Sunnybrook Odette Cancer Center, University of Toronto, Toronto, Ontario, Canada. Roberto.Pili@RoswellPark.org georg.bjarnason@utoronto.ca.
authors.forename: Georg A
authors.initials: GA
authors.lastname: Bjarnason
authors.affiliation: 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. Roberto.Pili@RoswellPark.org georg.bjarnason@utoronto.ca.
authors.forename: Roberto
authors.initials: R
authors.lastname: Pili
mesh_terms: D000818:Animals; D002292:Carcinoma, Renal Cell / Q000098:blood supply / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D018450:Disease Progression; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics; D000071221:Enhancer of Zeste Homolog 2 Protein; D044127:Epigenesis, Genetic / Q000187:drug effects; D006801:Humans; D007150:Immunohistochemistry; D007211:Indoles / Q000097:blood / Q000494:pharmacology / Q000627:therapeutic use*; D007680:Kidney Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D016513:Mice, SCID; D055806:Microvessels / Q000187:drug effects / Q000473:pathology; D063151:Polycomb Repressive Complex 2 / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D011758:Pyrroles / Q000097:blood / Q000494:pharmacology / Q000627:therapeutic use*; D000077210:Sunitinib; D016896:Treatment Outcome; D023041:Xenograft Model Antitumor Assays
chemical_list: D007211:Indoles; D047428:Protein Kinase Inhibitors; D011758:Pyrroles; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; D063151:Polycomb Repressive Complex 2; D000077210:Sunitinib