Rashid Narmeen S, Hairr Nicole S, Murray Graeme, Olex Amy L, Leftwich Tess J, Grible Jacqueline M, Reed Jason, Dozmorov Mikhail G, Harrell J Chuck
Department of Pathology, School of Medicine, Virginia Commonwealth University, 1101 East Marshall St, Office 4-007, P.O. Box 980662, Richmond, VA 23298-0662, USA; Department of Biology, University of Richmond, Richmond, VA USA.
Department of Pathology, School of Medicine, Virginia Commonwealth University, 1101 East Marshall St, Office 4-007, P.O. Box 980662, Richmond, VA 23298-0662, USA.
Transl Oncol. 2021 Dec;14(12):101235. doi: 10.1016/j.tranon.2021.101235. Epub 2021 Oct 7.
An estimated 284,000 Americans will be diagnosed with breast cancer in 2021. Of these individuals, 15-20% have basal-like triple-negative breast cancer (TNBC), which is known to be highly metastatic. Chemotherapy is standard of care for TNBC patients, but chemoresistance is a common clinical problem. There is currently a lack of alternative, targeted treatment strategies for TNBC; this study sought to identify novel therapeutic combinations to treat basal-like TNBCs. For these studies, four human basal-like TNBC cell lines were utilized to determine the cytotoxicity profile of 1363 clinically-used drugs. Ten promising therapeutic candidates were identified, and synergism studies were performed in vitro. Two drug combinations that included KPT-330, an XPO1 inhibitor, were synergistic in all four cell lines. In vivo testing of four basal-like patient-derived xenografts (PDX) identified one combination, KPT-330 and GSK2126458 (a PI3K/mTOR inhibitor), that decreased tumor burden in mice significantly more than monotherapy with either single agent. Bulk and single-cell RNA-sequencing, immunohistochemistry, and analysis of published genomic datasets found that XPO1 was abundantly expressed in human basal-like TNBC cell lines, PDXs, and patient tumor samples. Within basal-like PDXs, XPO1 overexpression was associated with increased proliferation at the cellular level. Within patient datasets, XPO1 overexpression was correlated with greater rates of metastasis in patients with basal-like tumors. These studies identify a promising potential new combination therapy for patients with basal-like breast cancer.
据估计，2021年将有28.4万美国人被诊断出患有乳腺癌。在这些患者中，15%-20%患有基底样三阴性乳腺癌（TNBC），已知这种癌症具有高度转移性。化疗是TNBC患者的标准治疗方法，但化疗耐药是一个常见的临床问题。目前缺乏针对TNBC的替代靶向治疗策略；本研究旨在确定治疗基底样TNBC的新型治疗组合。在这些研究中，使用了四种人类基底样TNBC细胞系来确定1363种临床使用药物的细胞毒性谱。确定了十种有前景的治疗候选药物，并进行了体外协同作用研究。两种包含XPO1抑制剂KPT-330的药物组合在所有四种细胞系中均具有协同作用。对四种基底样患者来源的异种移植瘤（PDX）进行的体内测试确定了一种组合，即KPT-330和GSK2126458（一种PI3K/mTOR抑制剂），与单药治疗相比，该组合能显著降低小鼠的肿瘤负担。大量和单细胞RNA测序、免疫组织化学以及对已发表基因组数据集的分析发现，XPO1在人类基底样TNBC细胞系、PDX和患者肿瘤样本中大量表达。在基底样PDX中，XPO1过表达与细胞水平的增殖增加相关。在患者数据集中，XPO1过表达与基底样肿瘤患者更高的转移率相关。这些研究为基底样乳腺癌患者确定了一种有前景的潜在新联合治疗方法。
