Laboratory of Toxicology and Safety Science, Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka, 565-0871, Japan.
Laboratory of Toxicology and Safety Science, Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka, 565-0871, Japan; Department of Legal Medicine, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan.
Biochem Biophys Res Commun. 2020 Dec 17;533(4):672-678. doi: 10.1016/j.bbrc.2020.09.143. Epub 2020 Oct 6.
Currently, the only therapeutic choice for the treatment of triple-negative breast cancer (TNBC) is chemotherapy. In TNBC, despite strong preclinical data, clinical trials of molecular targeted drugs, such as the Src tyrosine kinase inhibitor dasatinib, have failed because of the heterogeneity of TNBC cells. Here, we examined the mechanism of intrinsic resistance to dasatinib in five TNBC cell lines. First, we divided the TNBC cell lines into those sensitive or resistant to dasatinib and found that activation of Src was inhibited in all of the cell lines. In contrast, we found that dasatinib inhibited Akt phosphorylation in only the dasatinib-sensitive cell lines. Consequently, we found that combination treatment with dasatinib and an inhibitor of Akt or mTOR suppressed cell proliferation more than did either monotherapy in the dasatinib-resistant cell lines. Finally, to mimic intrinsic resistance, we established a dasatinib-tolerant TNBC cell line. In this cell line, the combinational effect of Akt/mTOR inhibition with dasatinib was observed, as it was in the cell lines with intrinsic resistance. Together, the present results show that the effect of dasatinib in TNBC is independent of Src inhibition, and that Akt/mTOR inhibition might be an effective strategy to overcome TNBC cells with intrinsic dasatinib resistance.
目前，治疗三阴性乳腺癌（TNBC）的唯一治疗选择是化疗。在 TNBC 中，尽管有强有力的临床前数据，但分子靶向药物的临床试验，如Src 酪氨酸激酶抑制剂 dasatinib，由于 TNBC 细胞的异质性而失败。在这里，我们研究了五种 TNBC 细胞系对 dasatinib 产生内在耐药性的机制。首先，我们将 TNBC 细胞系分为对 dasatinib 敏感或耐药的细胞系，发现所有细胞系中的 Src 激活均受到抑制。相比之下，我们发现 dasatinib 仅在 dasatinib 敏感的细胞系中抑制 Akt 磷酸化。因此，我们发现 dasatinib 和 Akt 或 mTOR 的抑制剂联合治疗在 dasatinib 耐药细胞系中比单独使用任何一种药物更能抑制细胞增殖。最后，为了模拟内在耐药性，我们建立了一个对 dasatinib 耐受的 TNBC 细胞系。在该细胞系中，观察到 Akt/mTOR 抑制与 dasatinib 的联合效应，与内在耐药性细胞系中的情况相同。总之，这些结果表明 dasatinib 在 TNBC 中的作用不依赖于 Src 抑制，Akt/mTOR 抑制可能是克服 TNBC 细胞内在 dasatinib 耐药性的有效策略。
