Signaling Networks Program, Division of Oncology, Department of Medicine I, Medical University Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria.
Breast Cancer Res Treat. 2011 Sep;129(2):387-400. doi: 10.1007/s10549-010-1232-1. Epub 2010 Nov 3.
Resistance against first and second generation (irreversible) ErbB inhibitors is an unsolved problem in clinical oncology. The purpose of this study was to examine the effects of the irreversible ErbB inhibitors pelitinib and canertinib on growth of breast and ovarian cancer cells. Although in vitro growth-inhibitory effects of both drugs exceeded by far the effects of all reversible ErbB blockers tested (lapatinib, erlotinib, and gefitinib), complete growth inhibition was usually not reached. To define the mechanism of resistance, we examined downstream signaling pathways in drug-exposed cells by Western blot analysis. Although ErbB phosphorylation was reduced by pelitinib and canertinib, activation of the AKT/mTOR pathway remained essentially unaltered in drug-resistant cells. Correspondingly, transfection of tumor cells with constitutively activated AKT was found to promote resistance against all ErbB inhibitors tested, whereas dominant negative AKT reinstalled sensitivity in drug-resistant cells. In a next step, we applied PI3K/AKT/mTOR blockers including the dual PI3K/mTOR kinase inhibitor NVP-BEZ235. These agents were found to cooperate with pelitinib and canertinib in producing in vitro growth inhibition in cancer cells resistant against ErbB-targeting drugs. In conclusion, our data show that ErbB drug-refractory activation of the PI3K/AKT/mTOR pathway plays a crucial role in resistance against classical and second-generation irreversible ErbB inhibitors, and NVP-BEZ235 can override this form of resistance against pelitinib and canertinib.
针对第一代和第二代（不可逆）ErbB 抑制剂的耐药性是临床肿瘤学尚未解决的问题。本研究旨在研究不可逆 ErbB 抑制剂培立替尼（pelitinib）和卡那替尼（canertinib）对乳腺癌和卵巢癌细胞生长的影响。虽然这两种药物在体外的生长抑制作用远远超过了所有测试的可逆 ErbB 阻滞剂（拉帕替尼、厄洛替尼和吉非替尼），但通常无法达到完全的生长抑制。为了明确耐药机制，我们通过 Western blot 分析检测了药物暴露细胞中的下游信号通路。尽管培立替尼和卡那替尼降低了 ErbB 磷酸化，但耐药细胞中 AKT/mTOR 通路的激活基本没有改变。相应地，转染肿瘤细胞中的组成性激活 AKT 被发现可促进对所有测试的 ErbB 抑制剂的耐药性，而显性失活 AKT 则可在耐药细胞中重新恢复对药物的敏感性。在下一步中，我们应用了包括双重 PI3K/mTOR 激酶抑制剂 NVP-BEZ235 在内的 PI3K/AKT/mTOR 阻滞剂。这些药物在产生对 ErbB 靶向药物耐药的癌细胞的体外生长抑制方面与培立替尼和卡那替尼具有协同作用。总之，我们的数据表明，PI3K/AKT/mTOR 通路的 ErbB 药物难治性激活在对抗经典和第二代不可逆 ErbB 抑制剂的耐药性中起着关键作用，NVP-BEZ235 可克服培立替尼和卡那替尼的这种耐药性。
