Renal cell carcinoma (RCC) is the most common malignancy of kidney and remains largely intractable once it recurs after resection. mTOR inhibitors have been one of the mainstays used against recurrent RCC; however, there has been a major problem of the resistance to mTOR inhibitors, and thus new combination treatments with mTOR inhibitors are required. We here retrospectively showed that regular use of antilipidemic drug statins could provide a longer progression free survival (PFS) in RCC patients prescribed with an mTOR inhibitor everolimus than without statins (median PFS, 7.5 months vs. 3.2 months, respectively; hazard ratio, 0.52; 95% CI, 0.22-1.11). In order to give a rationale for this finding, we used RCC cell lines and showed the combinatorial effects of an mTOR inhibitor with statins induced a robust activation of retinoblastoma protein, whose mechanisms were involved in statins-mediated hindrance of KRAS or Rac1 protein prenylation. Finally, statins treatment also enhanced the efficacy of an mTOR inhibitor in RCC xenograft models. Thus, we provide molecular and (pre)clinical data showing that statins use could be a drug repositioning for RCC patients to enhance the efficacy of mTOR inhibitors.
Cancer letters. 2018 May 17 [Epub ahead of print]
Nobuhisa Hagiwara, Motoki Watanabe, Mahiro Iizuka-Ohashi, Isao Yokota, Seijiro Toriyama, Mamiko Sukeno, Mitsuhiro Tomosugi, Yoshihiro Sowa, Fumiya Hongo, Kazuya Mikami, Jintetsu Soh, Akira Fujito, Hiroaki Miyashita, Yukako Morioka, Tsuneharu Miki, Osamu Ukimura, Toshiyuki Sakai
Department of Molecular-targeting Cancer Prevention, Kyoto Prefectural University of Medicine, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan; Department of Urology, Kyoto Prefectural University of Medicine, Japan., Department of Molecular-targeting Cancer Prevention, Kyoto Prefectural University of Medicine, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan. Electronic address: ., Department of Molecular-targeting Cancer Prevention, Kyoto Prefectural University of Medicine, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan; Department of Endocrine and Breast Surgery, Kyoto Prefectural University of Medicine, Japan., Department of Biostatistics, Kyoto Prefectural University of Medicine, Japan., Department of Urology, Kyoto Prefectural University of Medicine, Japan., Department of Molecular-targeting Cancer Prevention, Kyoto Prefectural University of Medicine, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan., Department of Urology, Japanese Red Cross Kyoto Daiichi Hospital, Honmachi, Higashiyama-ku, Kyoto, 605-0981, Japan., Department of Urology, Japanese Red Cross Kyoto Daini Hospital, Kamannza-marutamachi, Kamigyo-ku, Kyoto, 602-8026, Japan., Department of Urology, Saiseikai Suita Hospital, Kawazonocho, Suita, Osaka, 564-0013, Japan., Department of Urology, Omihachiman City Hospital, Tsuchida-cho, Omihachiman, Shiga, 523-0082, Japan., Department of Urology, Saiseikai shigaken Hospital, Ohashi, Ritto, Shiga, 520-3046, Japan.