PO.ET03.03 · 实验与分子治疗
理解并克服三阴性乳腺癌脑转移对RET单药治疗的耐药性
Understanding and overcoming resistance of triple-negative breast cancer brain metastases to RET monotherapy
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
乳腺癌是美国女性中最常见的癌症,预计2025年将有超过315,000例新发病例和超过42,000例死亡。三阴性乳腺癌(TNBC)是最具侵袭性的亚型,脑转移(BrainMet)发生率高,可达45%。临床研究显示,与肺、肝或骨转移患者相比,伴脑转移的TNBC患者生存时间最短(4-6个月)。这种不良预后主要归因于缺乏可用的治疗靶点和可穿透血脑屏障(BBB)的药物。目前尚未发现有效的TNBC脑转移疗法,凸显了对新型治疗方式的迫切需求。转染重排(RET)与非小细胞肺癌、甲状腺癌和乳腺癌的肿瘤发生和转移进展有关。口服的FDA获批RET抑制剂Pralsetinib和Selpercatinib已证明具有脑穿透性,在伴脑转移的肺癌患者中颅内应答率达70-91%,提示其可能用于治疗TNBC脑转移。在本研究中,我们探究了RET在TNBC脑转移中的作用,并评估了这些选择性RET抑制剂作为TNBC脑转移治疗的疗效。我们的数据挖掘分析显示,RET在TNBC脑转移患者中过度激活,并与更差的生存结局相关。在我们的心内注射和颅内接种小鼠模型中,TNBC细胞中RET的过表达促进了脑转移。在体内脑转移预防小鼠研究中,RET抑制剂治疗降低了肿瘤负荷和脑转移。然而,我们在体内脑转移治疗模型中观察到对RET抑制剂的耐药。我们还发现,与亲本TNBC细胞相比,脑亲和性TNBC细胞对RET抑制剂的敏感性较低。为鉴定潜在的耐药机制,我们进一步利用TCGA数据库分析,探究了乳腺癌脑转移中RET通路是否与其他致癌通路共激活。我们观察到RET与多种信号通路同时激活,包括t-GAS、VEGF、AKT和ERK。值得注意的是,共同抑制RET和这些信号通路在抑制脑亲和性TNBC细胞增殖方面产生了协同效应。我们的发现提示,这些共同抑制可能克服TNBC脑转移对RET单药治疗的耐药性。总之,靶向RET在预防性治疗中具有前景;共同抑制RET及其相关通路可能克服RET单药治疗耐药性,推进TNBC脑转移治疗,为未来针对伴脑转移的TNBC患者开展新型有效疗法的临床评估和开发提供临床前证据。
查看英文原文 English abstract
Breast cancer is the most common cancer among American women, with over 315,000 new cases and more than 42,000 deaths projected in 2025. Triple-negative breast cancer (TNBC), the most aggressive subtype, has a high incidence of brain metastasis (BrainMet)-up to 45%. Clinical studies show that TNBC patients with BrainMet have the shortest survival times (4-6 months) compared to those with lung, liver, or bone metastases. This poor prognosis is mainly due to a lack of actionable therapeutic targets and blood-brain barrier (BBB)-permeable drugs. No effective TNBC-BrainMet therapeutics have been identified, underscoring the urgent need for novel treatment modalities. Rearranged during transfection (RET) is implicated in tumorigenesis and metastatic progression in non-small cell lung cancers, thyroid carcinoma, and breast cancers. The orally FDA-approved RET inhibitors, Pralsetinib and Selpercatinib, demonstrated brain penetration, with 70-91% intracranial response rates in lung cancer patients with BrainMet, suggesting their possible utility in treating TNBC-BrainMet. In this study, we investigated the role of RET in TNBC-BrainMet and assessed the therapeutic efficacy of these selective RET inhibitors as a TNBC-BrainMet treatment. Our datamining analyses revealed that RET is hyperactivated in TNBC-BrainMet patients and is associated with worsened survival outcomes. Overexpression of RET in TNBC cells promoted brain metastasis in our intracardiac injection and intracranial inoculation mouse models. Treatment with RET inhibitors reduced tumor burden and brain metastasis in the BrainMet prevention mouse study in vivo . However, we observed drug resistance to RET inhibitors in the BrainMet treatment model in vivo . We also found lower sensitivity to RET inhibitors in brain-tropic TNBC cells compared to parental TNBC cells. To identify the potential mechanisms of resistance, we further investigated whether RET pathway is co-activated with other oncogenic pathways in breast cancer brain metastasis using the TCGA database analyses. We observed that RET is concurrently activated with multiple signaling pathways, including t-GAS, VEGF, AKT, and ERK. Notably, co-inhibition of RET and these signaling pathways produced synergistic effects in suppressing the proliferation of brain-tropic TNBC cells. Our findings suggested that these co-inhibitions may overcome RET monotherapy resistance in TNBC-BrainMet. In summary, targeting RET is promising for preventive therapy; co-inhibition of RET and its associated pathways may overcome RET monotherapy resistance and advance TNBC-BrainMet treatment, providing preclinical evidence to support future clinical evaluation and development of new effective therapies for TNBC patient with brain metastasis.
利益披露 Disclosure
P. Tran, None..
E. Bloom, None..
A. Regua, None..
S. Bindal, None..
M. Najja, None..
S. Syed, None..
H. Lo, None.