Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA; Center for Cancer Precision Medicine, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Cell Rep. 2019 Mar 5;26(10):2667-2680.e7. doi: 10.1016/j.celrep.2019.02.023.
CDK4/6 inhibition is now part of the standard armamentarium for patients with estrogen receptor-positive (ER) breast cancer, so that defining mechanisms of resistance is a pressing issue. Here, we identify increased CDK6 expression as a key determinant of acquired resistance after palbociclib treatment in ER breast cancer cells. CDK6 expression is critical for cellular survival during palbociclib exposure. The increased CDK6 expression observed in resistant cells is dependent on TGF-β pathway suppression via miR-432-5p expression. Exosomal miR-432-5p expression mediates the transfer of the resistance phenotype between neighboring cell populations. Levels of miR-432-5p are higher in primary breast cancers demonstrating CDK4/6 resistance compared to those that are sensitive. These data are further confirmed in pre-treatment and post-progression biopsies from a parotid cancer patient who had responded to ribociclib, demonstrating the clinical relevance of this mechanism. Finally, the CDK4/6 inhibitor resistance phenotype is reversible in vitro and in vivo by a prolonged drug holiday.
CDK4/6 抑制现已成为雌激素受体阳性（ER）乳腺癌患者的标准治疗方法之一，因此明确耐药机制是当务之急。在此，我们发现 CDK6 表达增加是 ER 乳腺癌细胞在 palbociclib 治疗后获得性耐药的关键决定因素。CDK6 表达对于 palbociclib 暴露期间的细胞存活至关重要。在耐药细胞中观察到的 CDK6 表达增加依赖于 TGF-β 通路抑制，通过 miR-432-5p 表达实现。外泌体 miR-432-5p 表达介导耐药表型在相邻细胞群体之间的转移。与敏感的原发性乳腺癌相比，表现出 CDK4/6 耐药性的原发性乳腺癌中 miR-432-5p 的水平更高。这些数据在接受 ribociclib 治疗的腮腺癌患者的治疗前和进展后活检中得到进一步证实，证明了该机制的临床相关性。最后，通过延长药物停药期，在体外和体内均可逆转 CDK4/6 抑制剂耐药表型。
