Preclinical evaluation of a novel triple-acting PIM/PI3K/mTOR inhibitor, IBL-302, in breast cancer
Preclinical evaluation of a novel triple-acting PIM/PI3K/mTOR inhibitor, IBL-302, in breast cancer
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DOI：
10.1038/s41388-020-1202-y
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发表时间：
2020-02-10
期刊：
影响因子：
8
通讯作者：
Hennessy, Bryan T.
中科院分区：
文献类型：
--
作者：
Kennedy, Sean P.;O'Neill, Michael;Hennessy, Bryan T.
莫洛尼病毒（PIM）家族蛋白激酶的前病毒整合在许多血液病和实体肿瘤中过度表达。PI3K抑制剂治疗的乳腺癌样本中PIM激酶表达升高，提示PI3K抑制剂在乳腺癌中的主要耐药途径，可能限制其临床应用。IBL-302是一种抑制PIM和PI3K/AKT/mTOR信号传导的新型分子。因此，我们在一系列乳腺癌模型中评估了IBL-302的临床前活性。我们的研究结果证明了IBL-302对一系列乳腺癌细胞系的体外疗效，包括对曲妥珠单抗和拉帕替尼具有获得性耐药的细胞系。IBL-302在SKBR-3、BT-474和HCC-1954 HER2+/ pik3ca突变细胞系中显示出单药抗肿瘤作用，抑制pAKT、pmTOR和pBAD。我们还在BALB/c裸鼠皮下BT-474和HCC-1954异种移植模型中显示了IBL-302的体内单药疗效。与单独测试任何一种药物相比，曲妥珠单抗和IBL-302联合使用显著提高了HER2+乳腺癌细胞系的抗增殖作用，并匹配了曲妥珠单抗耐药细胞系。因此，我们认为，新的PIM和PI3K/mTOR抑制剂IBL-302代表了一种令人兴奋的新的潜在治疗乳腺癌的选择，应该考虑进行临床研究。
The proviral integration of Moloney virus (PIM) family of protein kinases are overexpressed in many haematological and solid tumours. PIM kinase expression is elevated in PI3K inhibitor-treated breast cancer samples, suggesting a major resistance pathway for PI3K inhibitors in breast cancer, potentially limiting their clinical utility. IBL-302 is a novel molecule that inhibits both PIM and PI3K/AKT/mTOR signalling. We thus evaluated the preclinical activity of IBL-302, in a range of breast cancer models. Our results demonstrate in vitro efficacy of IBL-302 in a range of breast cancer cell lines, including lines with acquired resistance to trastuzumab and lapatinib. IBL-302 demonstrated single-agent, anti-tumour efficacy in suppression of pAKT, pmTOR and pBAD in the SKBR-3, BT-474 and HCC-1954 HER2+/PIK3CA-mutated cell lines. We have also shown the in vivo single-agent efficacy of IBL-302 in the subcutaneous BT-474 and HCC-1954 xenograft model in BALB/c nude mice. The combination of trastuzumab and IBL-302 significantly increased the anti-proliferative effect in HER2+ breast cancer cell line, and matched trastuzumab-resistant line, relative to testing either drug alone. We thus believe that the novel PIM and PI3K/mTOR inhibitor, IBL-302, represents an exciting new potential treatment option for breast cancer, and that it should be considered for clinical investigation.