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对化疗耐药的三阴性乳腺癌患者预后不良、肿瘤复发风险较高。这些高度恶性的表现，部分归咎于乳腺癌干细胞。因此，靶向乳腺癌干细胞是克服三阴性乳腺癌化疗失败的当务之急。 2018年11月28日，英国癌症研究基金会和英国《自然》旗下《英国癌症杂志》在线发表加拿大蒙特利尔麦吉尔大学和圣玛丽医院的研究报告，发现达沙替尼通过靶向乳腺癌干细胞，可使三阴性乳腺癌细胞对化疗敏感。达沙替尼已于2006年被批准用于治疗对伊马替尼耐药或不耐受的费城染色体阳性白血病，已被列入世界卫生组织基本药物标准清单，2017年进入中国国家基本医疗保险、工伤保险和生育保险药品目录。 该研究首先培育出对紫杉醇耐药的三阴性乳腺癌细胞，这些细胞与亲代细胞相比，肿瘤形成能力和乳腺癌干细胞比例较高。随后，该研究对各种激酶抑制剂进行筛选，发现原癌基因Src酪氨酸激酶抑制剂达沙替尼可以有效抑制紫杉醇耐药三阴性乳腺癌细胞的乳腺癌干细胞扩增和肿瘤形成。 机理分析表明，达沙替尼可以阻断紫杉醇诱发的乳腺癌干细胞富集、亲代细胞和紫杉醇耐药三阴性乳腺癌细胞的Src活化。有趣的是，达沙替尼还可诱发紫杉醇耐药间质细胞向良性上皮细胞转化，增强其对紫杉醇的敏感性。达沙替尼联合紫杉醇不仅可以抑制乳腺癌干细胞数量及其肿瘤形成能力，而且可以协同抑制紫杉醇耐药细胞的生存生长能力。临床前人类乳腺肿瘤移植小鼠模型进一步证实了达沙替尼联合紫杉醇抑制肿瘤生长的效果。 因此，该研究结果表明，达沙替尼有望作为抗乳腺癌干细胞药物，与紫杉醇联合使用，克服三阴性乳腺癌的化疗耐药。 注：本文并非科普文章，仅供专业人士参考，切忌向无专业知识的读者转发，以免不必要的误读和误解，谢谢！ Br J Cancer. 2018 Nov 28. [Epub ahead of print] Dasatinib sensitises triple negative breast cancer cells to chemotherapy by targeting breast cancer stem cells. Jun Tian, Fatmah Al Raffa, Meiou Dai, Alaa Moamer, Baharak Khadang, Ibrahim Y. Hachim, Khldoun Bakdounes, Suhad Ali, Bertrand Jean-Claude, Jean-Jacques Lebrun. McGill University Health Center, Montreal, Quebec, Canada; St. Mary's Hospital, Montreal, Quebec, Canada. BACKGROUND: Patients with triple negative breast cancer (TNBC) exhibit poor prognosis and are at high risk of tumour relapse, due to the resistance to chemotherapy. These aggressive phenotypes are in part attributed to the presence of breast cancer stem cells (BCSCs). Therefore, targeting BCSCs is a priority to overcoming chemotherapy failure in TNBCs. METHODS: We generated paclitaxel (pac)-resistant TNBC cells which displayed higher sphere forming potential and percentage of BCSC subpopulations compared to the parental cells. A screen with various kinase inhibitors revealed dasatinib, a Src kinase family inhibitor, as a potent suppressor of BCSC expansion/sphere formation in pac-resistant TNBC cells. RESULTS: We found dasatinib to block pac-induced BCSC enrichment and Src activation in both parental and pac-resistant TNBC cells. Interestingly, dasatinib induced an epithelial differentiation of the pac-resistant mesenchymal cells, resulting in their enhanced sensitivity to paclitaxel. The combination treatment of dasatinib and paclitaxel not only decreased the BCSCs numbers and their sphere forming capacity but also synergistically reduced cell viability of pac-resistant cells. Preclinical models of breast cancer further demonstrated the efficiency of the dasatinib/paclitaxel combination treatment in inhibiting tumour growth. CONCLUSIONS: Dasatinib is a promising anti-BCSC drug that could be used in combination with paclitaxel to overcome chemoresistance in TNBC. DOI: 10.1038/s41416-018-0287-3
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