1. Academic Validation
  2. Rational Combination Therapy for Melanoma with Dinaciclib by Targeting BAK-Dependent Cell Death

Rational Combination Therapy for Melanoma with Dinaciclib by Targeting BAK-Dependent Cell Death

  • Mol Cancer Ther. 2020 Feb;19(2):627-636. doi: 10.1158/1535-7163.MCT-19-0451.
Xiaoou Xu 1 Shizuka Eshima 1 Shinichiro Kato 1 2 David E Fisher 2 Hiroaki Sakurai 3 Yoshihiro Hayakawa 1 Satoru Yokoyama 4 3
Affiliations

Affiliations

  • 1 Division of Pathogenic Biochemistry, Institute of Natural Medicine, University of Toyama, Toyama, Japan.
  • 2 Department of Dermatology, Cutaneous Biology Research Center, Massachusetts General Hospital, Harvard Medical School, Massachusetts.
  • 3 Department of Cancer Cell Biology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan.
  • 4 Division of Pathogenic Biochemistry, Institute of Natural Medicine, University of Toyama, Toyama, Japan. yokoyama@pha.u-toyama.ac.jp.
Abstract

Mutation of the oncogene BRaf is among the most common genetic alterations in melanoma. BRaf inhibitors alone or in combination with MEK inhibitors fail to eradicate the tumor in most patients due to combinations of intrinsic or acquired resistance. Therefore, novel strategies are needed to improve the therapeutic efficacy of BRaf inhibition. We demonstrated that dinaciclib has potent antimelanoma effects by inducing BAK-dependent Apoptosis through MCL1 reduction. Contrary to dinaciclib, the inhibitors of BRaf/MEK/CDK4/6 induced Apoptosis dominantly through a BAX-dependent mechanism. Although the combination of BRaf and MEK inhibitors did not exhibit additive antimelanoma effects, their combination with dinaciclib synergistically inhibited melanoma growth both in vitro and in vivo Collectively, our present findings suggest dinaciclib to be an effective complementary drug of BAX-dependent antimelanoma drugs by targeting BAK-mediated Apoptosis, and other such rational drug combinations can be determined by identifying complementary drugs activating either Bak or Bax.

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