Midostaurin (PKC412)は経口で、多標的チロシンキナーゼ阻害剤であり、FLT3、KIT、PDGFRやVEGFR (IC50 = 22-500nM)など複数のキナーゼを阻害する[1-2]。MidostaurinはATPとキナーゼの結合を競合的に阻害し、よって腫瘍細胞の増殖を遮断し、アポトーシスを促進する[3]。Midostaurinはよく、FLT3変異を持つ、急性骨髄性白血病（AML）の治療に使われる[4]。
末梢血単核細胞(PBMCs)で、Midostaurin (1µM; 72h)は、CD4+CD25+FOXP3+ T細胞集団とFOXP3 mRNAの発見を著しく減らした[5]。MDA -MB-468細胞で、Midostaurin (1µM; 72h)はAuroraキナーゼAとBを直接的に阻害し、その後は、TNBC細胞で、細胞の生存率を減らした[6]。HMC-1細胞で、ponatinibはMidostaurin (0-0.1µM; 48h)と併用し、成長の阻害とアポトーシスを誘発する[7]。
CT26細胞異種移植腫瘍マウスモデルで、Midostaurin (100mg/kg; po; 7d)の処理は、腫瘍の成長を著しく阻害した[8]。HL-60細胞異種移植腫瘍マウスモデルで、オールトランスレチノイン酸とMidostaurin (50mg/kg; po; 10d)の併用処理は、腫瘍の成長を著しく阻害した[9]。
References:
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[2]. Fabbro D, Ruetz S, Bodis S, et al. PKC412-a protein kinase inhibitor with a broad therapeutic potential[J]. Anti-cancer drug design, 2000, 15(1): 17-28.
[3]. Gallogly M M, Lazarus H M, Cooper B W. Midostaurin: a novel therapeutic agent for patients with FLT3-mutated acute myeloid leukemia and systemic mastocytosis[J]. Therapeutic advances in hematology, 2017, 8(9): 245-261.
[4]. Levis M. Midostaurin approved for FLT3-mutated AML[J]. Blood, The Journal of the American Society of Hematology, 2017, 129(26): 3403-3406.
[5]. Gutierrez L, Jang M, Zhang T, et al. Midostaurin reduces regulatory T cells markers in acute myeloid leukemia[J]. Scientific reports, 2018, 8(1): 17544.
[6]. Kawai M, Nakashima A, Kamada S, et al. Midostaurin preferentially attenuates proliferation of triple-negative breast cancer cell lines through inhibition of Aurora kinase family[J]. Journal of biomedical science, 2015, 22(1): 48.
[7]. Gleixner K V, Peter B, Blatt K, et al. Synergistic growth-inhibitory effects of ponatinib and midostaurin (PKC412) on neoplastic mast cells carrying KIT D816V[J]. Haematologica, 2013, 98(9): 1450.
[8]. Lai C T, Chi C W, Wu S H, et al. Midostaurin modulates tumor microenvironment and enhances efficacy of anti-PD-1 against colon cancer[J]. Cancers, 2022, 14(19): 4847.
[9]. Lu H, Weng X, Sheng Y, et al. Combination of midostaurin and ATRA exerts dose-dependent dual effects on acute myeloid leukemia cells with wild type FLT3[J]. BMC cancer, 2022, 22(1): 749.