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 clinical efficacy, eventually patients 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 (PDXs) were treated 5 days/week with a dose-escalation schema (40-60-80 mg/kg sunitinib). Tumor tissues were collected prior to dose increments for immunohistochemistry analyses and drug levels. Selected intra-patient 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 anti-tumor 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.

Dual modulation of MCL-1 and mTOR determines the response to sunitinib

“…This dual mechanism thus not only can contribute to resistance to sunitinib, but also can represent a mechanism by which higher doses of sunitinib exert cytotoxicity. Several reports have shown that cancer patients who resisted and subsequently progressed in response to clinically approved doses of sunitinib as well as during "sunitinib-off " period can be sensitized to sunitinib by escalating its dose (11,48). Our data shown here provide a potential molecular explanation for this reported observation, as higher doses of sunitinib could shift the response of tumor cells toward MCL-1 destabilization and mTOR inhibition, with an increased anticancer effect.…”

“…Sunitinib is approved for treating patients with advanced renal cell carcinoma (2), pancreatic neuroendocrine tumors (3), and gastrointestinal stromal tumors (4,5) and is being tested in other types of cancer including osteosarcoma (6), colorectal cancer (7), and melanoma (8). However, a substantial percentage of patients are intrinsically resistant to sunitinib, and most patients who show initial response to treatment with sunitinib eventually relapse and develop progressive disease secondary to acquired sunitinib resistance, resulting in a modest overall therapeutic benefit (9)(10)(11)(12)(13). Optimal clinical use of sunitinib therefore relies on better understanding of the mechanisms of tumor resistance to this anticancer agent.…”

Kidney Cancer Research Network of Canada (KCRNC) consensus statement on the role of adjuvant therapy after nephrectomy for high-risk, non-metastatic renal cell carcinoma: A comprehensive analysis of the literature and meta-analysis of randomized controlled trials

“…This observation may at least in part explain better DFS benefit of sunitinib in S-TRAC, relative to that reported in the ASSURE trial. In consequence, dose escalations such as described by Bjarnason et al [11,12], might result in better DFS and possibly also in better OS and dose individualization may warrant consideration, if adjuvant sunitinib therapy is considered.…”

Can individualized sunitinib dose and schedule changes optimize outcomes for kidney cancer patients?

“…6 This may explain the clinical observation of reduced toxicity as patients stay on tyrosine kinase inhibitor (TKI) therapy. These observations led to our early attempts to individualize dose and schedule to toxicity, 7,8 assuming toxicity might correlate better with sunitinib pharmacodynamics (PD) 9 and would take into account the inter-individual differences in sunitinib PK, potential decline in PK over time, individual singlenucleotide polymorphisms, and interactions with other drugs and that can impact the PK for sunitinib.…”