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Activation of BAX and BAK is an attractive combination therapy in melanoma

徐 小鴎 富山大学

2020.03.24

概要

Cancer therapy has been developed in the last several decades from non-specific cytotoxic chemotherapy to specific targeted therapeutics. One of the most important progressions in melanoma therapy is the discovery of BRAF inhibitors, including vemurafenib, which led to significant clinical responses in melanoma. However, it fails to eradicate tumors in nearly all patients due to short-lived responses and drug resistance, and almost all patients eventually relapse. Therefore, novel strategies are still required for melanoma therapy.

Defective apoptosis in cancers can impair clinical responses to anti-cancer therapy. Pro-apoptotic BCL-2 proteins, BAX and BAK, are known as critical effectors for intrinsic apoptosis; however, how BAX and BAK cooperate to determine cell death are still remain unclear and their roles are overlapping or redundant. In this study, I highlight that activation of both BAX and BAK contribute to cancer cell death induced by many apoptotic stimulation. A better understanding of BAX/BAK dependency of each anti-cancer reagent might be helpful to determine more effective response in cancer therapy.

Chapter 1. Coptidis Rhizoma induces intrinsic apoptosis through BAX and BAK activation in human melanoma( 論 文 1)
Traditional herbal medicines have been found to have anti-cancer effects in various types of cancer including melanoma in recent years. In chapter 1, I determined that a traditional herbal medicine, Coptidis Rhizoma water extracts (CR), suppressed melanoma cell growth thorough apoptosis, which was regulated by the suppression of MCL1, BCL2A1 and BCL-w, resulting in the activation of BAX/BAK. CR or some formulations containing CR, may be effective and safe treatment strategies for melanoma.

Chapter 2. Rational combination therapy for melanoma with CDK2/9 inhibition by targeting BAK-dependent cell death(論文 2)
BRAF inhibitor, vemurafenib, is widely used to treat melanoma patients as monotherapy or in combination in clinical therapeutics. Vemurafenib has been reported to induce modest apoptosis in melanoma cells; however, the mechanism underlying it has been well understood yet. In chapter 2, I demonstrated that BAX is indispensable for BRAF/MEK inhibitor-induced melanoma apoptosis. After the screening of chemotherapeutic agent library, I found two CDK2/9 inhibitors, dinaciclib and iCDK2/9, as the drugs inducing apoptosis at a BAK-dependent manner through MCL1 reduction. Although vemurafenib with MEK inhibitor, trametinib, could not strongly suppress cell growth in vitro, the combination of dinaciclib with BAX-activating drugs synergistically inhibited melanoma growth in vitro and in vivo. Finally, I proposed a rational combination of BAK-dependent CDK2/9 inhibitor with BAX-dependent drugs, such as BRAF/MEK inhibitor, might be an attractive strategy for treating melanoma, proposing the novel theory to determine the rational combination using two molecular-targeted drugs activating either BAK or BAX, respectively.

Collectively, these studies present the potential use of targeting BAX/BAK as a rational therapeutic strategy for different cancer including melanoma.

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