Ishikura Nobuyuki, Sugimoto Masamichi, Yorozu Keigo, Kurasawa Mitsue, Wakita Daiko, Kondoh Osamu
Product Research Department, Chugai Pharmaceutical Co., Ltd., Kanagawa, Japan.
Cancer Diagn Progn. 2022 Sep 3;2(5):533-541. doi: 10.21873/cdp.10138. eCollection 2022 Sep-Oct.
BACKGROUND/AIM: Although CDK4/6 inhibitors have been increasingly used in combination with hormonal agents to treat hormone-receptor positive and human epithelial growth factor receptor 2-negative breast cancer, the mechanism of CDK4/6 inhibitor resistance and its impact on established therapy for post-resistance, especially bevacizumab combined with chemotherapy, are unclear.
Sensitivity of RB knockout MCF7 clones to CDK4/6 inhibitors was evaluated in vitro. One RB knockout clone was subcutaneously implanted in nude mice and the effects of bevacizumab on volume and microvessel density (MVD) of tumors were investigated.
Palbociclib did not exhibit antitumor efficacy against the RB knockout tumor, in contrast to the parental MCF7 xenograft model. Bevacizumab significantly exhibited antitumor efficacy and suppressed the MVD both in RB knockout and parental MCF7 xenograft models.
Bevacizumab inhibited tumor growth by suppressing MVD in the CDK4/6 inhibitor-resistant tumor acquired due to RB loss, suggesting its efficacy also in patients after treatment with CDK4/6 inhibitors.
背景/目的：尽管细胞周期蛋白依赖性激酶4/6（CDK4/6）抑制剂已越来越多地与激素药物联合用于治疗激素受体阳性且人表皮生长因子受体2阴性的乳腺癌，但CDK4/6抑制剂耐药的机制及其对耐药后既定治疗（尤其是贝伐单抗联合化疗）的影响尚不清楚。
在体外评估RB基因敲除的MCF7克隆对CDK4/6抑制剂的敏感性。将一个RB基因敲除克隆皮下植入裸鼠体内，研究贝伐单抗对肿瘤体积和微血管密度（MVD）的影响。
与亲本MCF7异种移植模型相比，帕博西尼对RB基因敲除肿瘤未表现出抗肿瘤疗效。在RB基因敲除和亲本MCF7异种移植模型中，贝伐单抗均显著表现出抗肿瘤疗效并抑制了MVD。
贝伐单抗通过抑制因RB缺失而获得的CDK4/6抑制剂耐药肿瘤中的MVD来抑制肿瘤生长，提示其在CDK4/6抑制剂治疗后的患者中也有效。
