背景:用芳香化酶抑制剂(AI)治疗的乳腺癌可以产生AI耐药性,通常由雌激素受体α(ERα/ESR1)激活突变驱动,以及不依赖ER的信号通路。乳房内质网拮抗剂拉索福昔芬,单独或与palbociclib联合使用,在具有ESR1突变的ER转移性乳腺癌(mBC)的异种移植模型中引发了抗肿瘤活性。目前的研究调查了LAS在不具有ESR1突变的来曲唑耐药乳腺肿瘤模型中的活性。
方法:来曲唑耐药,将用荧光素酶-GFP标记的MCF7LTLT细胞注射到NSG小鼠的乳腺导管腹股沟腺中(MIND模型;6只小鼠/组)。将小鼠随机分配到媒介物中,拉索福昔芬±palbociclib,氟维司群±palbociclib,细胞注射后2-3周或单独palbociclib。用体内和离体发光成像监测肿瘤生长和转移,最终肿瘤重量测量,和组织学分析。用相同的设计和每个处理组中的8-9只小鼠重复实验。
结果:Western印迹分析表明,与正常MCF7细胞相比,MCF7LTLT细胞具有更低的ERα和更高的HER2表达。Lasofoxifene±palbociclib,但不是Fulvestrant,研究结束时通过体内肿瘤成像评估,与载体相比,原发性肿瘤生长显着降低。与媒介物相比,拉索福昔芬加palbociclib切除的乳腺中的肿瘤面积百分比显着降低。Ki67染色显示,拉索福昔芬±palbociclib降低了肿瘤细胞的整体增殖。与媒介物相比,拉索福昔芬+帕博西尼组合也与显著更少的骨转移相关。在重复实验中观察到类似的结果。
结论:在没有ESR1突变的来曲唑耐药乳腺癌小鼠模型中,降低ERα水平,和HER2的过度表达,单独使用拉索福昔芬或与palbociclib联合使用比氟维司群更有效地抑制原发性肿瘤的生长。拉索福昔芬联合帕博西尼也能减少骨转移。这些结果表明,单独使用拉索福昔芬或与CDK4/6抑制剂联合使用可能对ER低和HER2阳性的患者有益。抗AI乳腺癌,与ESR1突变无关。
BACKGROUND: Breast cancers treated with aromatase inhibitors (AIs) can develop AI resistance, which is often driven by estrogen receptor-alpha (ERα/ESR1) activating mutations, as well as by ER-independent signaling pathways. The breast ER antagonist lasofoxifene, alone or combined with palbociclib, elicited antitumor activities in a xenograft model of ER + metastatic breast cancer (mBC) harboring ESR1 mutations. The current study investigated the activity of LAS in a letrozole-resistant breast tumor model that does not have ESR1 mutations.
METHODS: Letrozole-resistant, MCF7 LTLT cells tagged with luciferase-GFP were injected into the mammary duct inguinal glands of NSG mice (MIND model; 6 mice/group). Mice were randomized to vehicle, lasofoxifene ± palbociclib, fulvestrant ± palbociclib, or palbociclib alone 2-3 weeks after cell injections. Tumor growth and metastases were monitored with in vivo and ex vivo luminescence imaging, terminal tumor weight measurements, and histological analysis. The experiment was repeated with the same design and 8-9 mice in each treatment group.
RESULTS: Western blot analysis showed that the MCF7 LTLT cells had lower ERα and higher HER2 expressions compared with normal MCF7 cells. Lasofoxifene ± palbociclib, but not fulvestrant, significantly reduced primary tumor growth versus vehicle as assessed by in vivo imaging of tumors at study ends. Percent tumor area in excised mammary glands was significantly lower for lasofoxifene plus palbociclib versus vehicle. Ki67 staining showed decreased overall tumor cell proliferation with lasofoxifene ± palbociclib. The lasofoxifene + palbociclib combination was also associated with significantly fewer bone metastases compared with vehicle. Similar results were observed in the repeat experiment.
CONCLUSIONS: In a mouse model of letrozole-resistant breast cancer with no ESR1 mutations, reduced levels of ERα, and overexpression of HER2, lasofoxifene alone or combined with palbociclib inhibited primary tumor growth more effectively than fulvestrant. Lasofoxifene plus palbociclib also reduced bone metastases. These results suggest that lasofoxifene alone or combined with a CDK4/6 inhibitor may offer benefits to patients who have ER-low and HER2-positive, AI-resistant breast cancer, independent of ESR1 mutations.