Preclinical evaluation of the mTOR inhibitor, temsirolimus, in combination with the epothilone B analog, ixabepilone in renal cell carcinoma.

Historically, metastatic renal cell carcinoma (mRCC) is more resistant to conventional cytotoxic chemotherapeutic agents than other solid tumors. Although significant progress has been made over the last decade with several novel therapeutics, these agents invariably go on to fail, largely due to either intrinsic or acquired resistance. To help overcome, or at least delay resistance, combinatorial therapies utilizing agents with disparate, and ideally complementary, mechanisms of actions are needed. In this report, we assess the novel combination of the mTOR inhibitor, temsirolimus, with the microtubule stabilizing drug ixabepilone in RCC. Our results demonstrate synergy in multiple cell lines of RCC and further evaluation of this combination is warranted in the clinical setting. Activation of the endoplasmic reticulum (ER) stress response pathway may in part explain the combinatorial synergy. We further propose that ER stress induced proteins may serve as early response biomarkers to combinatorial therapy in a clinical trial.