Vivian L. Smith Department of Neurosurgery, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, USA; Graduate School of Biomedical Sciences, The University of Texas Health Science Center at Houston, Houston, TX, USA.
Vivian L. Smith Department of Neurosurgery, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, USA.
Cancer Lett. 2024 Aug 10;597:217023. doi: 10.1016/j.canlet.2024.217023. Epub 2024 Jun 7.
HER2-positive and triple-negative breast cancers (TNBC) are difficult to treat and associated with poor prognosis. Despite showing initial response, HER2-positive breast cancers often acquire resistance to HER2-targeted therapies, and TNBC lack effective therapies. To overcome these clinical challenges, we evaluated the therapeutic utility of co-targeting TrkA and JAK2/STAT3 pathways in these breast cancer subtypes. Here, we report the novel combination of FDA-approved TrkA inhibitors (Entrectinib or Larotrectinib) and JAK2 inhibitors (Pacritinib or Ruxolitinib) synergistically inhibited in vitro growth of HER2-positive breast cancer cells and TNBC cells. The Entrectinib-Pacritinib combination inhibited the breast cancer stem cell subpopulation, reduced expression of stemness genes, SOX2 and MYC, and induced apoptosis. The Entrectinib-Pacritinib combination suppressed orthotopic growth of HER2-positive Trastuzumab-refractory breast cancer xenografts and basal patient-derived xenograft (PDXs), reduced tumoral SOX2 and MYC, and induced apoptosis in both mouse models. The Entrectinib-Pacritinib combination inhibited overall metastatic burden, and brain and bone metastases of intracardially inoculated TNBC cells without toxicity. Together, our results demonstrate for the first time that co-inhibition of TrkA and JAK2 synergistically suppresses breast cancer growth and metastasis, thereby providing preclinical evidence that supports future clinical evaluations.
HER2 阳性和三阴性乳腺癌（TNBC）难以治疗，预后不良。尽管 HER2 阳性乳腺癌最初显示出反应，但经常获得对 HER2 靶向治疗的耐药性，而 TNBC 缺乏有效治疗方法。为了克服这些临床挑战，我们评估了共同靶向 TrkA 和 JAK2/STAT3 通路在这些乳腺癌亚型中的治疗效用。在这里，我们报告了 FDA 批准的 TrkA 抑制剂（Entrectinib 或 Larotrectinib）和 JAK2 抑制剂（Pacritinib 或 Ruxolitinib）的新型联合使用，可协同抑制 HER2 阳性乳腺癌细胞和 TNBC 细胞的体外生长。Entrectinib-Pacritinib 联合抑制乳腺癌干细胞亚群，降低干细胞基因 SOX2 和 MYC 的表达，并诱导细胞凋亡。Entrectinib-Pacritinib 联合抑制 HER2 阳性曲妥珠单抗耐药性乳腺癌异种移植瘤和基底患者来源异种移植瘤（PDX）的原位生长，降低肿瘤 SOX2 和 MYC，并在两种小鼠模型中诱导细胞凋亡。Entrectinib-Pacritinib 联合抑制心脏内接种的 TNBC 细胞的总转移负担，以及脑和骨转移，而没有毒性。总之，我们的研究结果首次表明，共同抑制 TrkA 和 JAK2 可协同抑制乳腺癌的生长和转移，从而为支持未来临床评估的提供了临床前证据。
