PO.TB09.02 · 肿瘤生物学
迈向精准肿瘤学的演进：利用附带药物反应实现个体化二线骨肉瘤治疗
Evolving toward precision oncology: Leveraging collateral drug responses for personalized second-line osteosarcoma treatment
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
目的：我们旨在体外模拟对甲氨蝶呤、多柔比星和顺铂(MAP)化疗耐药的演化过程，并表征随时间变化的附带药物敏感性和耐药模式，从而为化疗耐药的原发或复发疾病的二线治疗策略提供潜在信息。
方法：对MG63.3骨肉瘤细胞的五个演化重复，采用六个完整周期的脉冲式、临床相关剂量的顺铂和多柔比星，与甲氨蝶呤交替进行处理。每个化疗周期后进行剂量-反应曲线检测，以评估对MAP的耐药性以及对16种药物及组合的附带反应。在各治疗时间点进行RNA测序和转录因子活性推断，以在时间上探索药物反应的转录相关因素。
结果：细胞对多柔比星(1.49-2.59倍)和甲氨蝶呤(0.92-2.87倍)产生耐药，但对顺铂仍保持敏感。对依托泊苷、长春新碱和拓扑替康出现附带耐药，而对吉西他滨、卡博替尼和帕利福斯酰胺的敏感性增加。附带反应随时间变化各异，一些随MAP耐药性演化呈线性增加，一些则表现为短暂或随机。转录谱分析揭示E2F和ERG活性增加，以及干扰素信号的情境依赖性作用。耐药表型在停药和冷冻保存后持续存在。
结论：我们的模型揭示了骨肉瘤在对MAP化疗耐药发展过程中随时间动态变化的异质性附带反应。虽然出现了对多种药物的交叉耐药，但对吉西他滨和卡博替尼的附带敏感性支持将这些药物用于二线治疗。这些数据可为合理的治疗序贯提供信息，以预先阻止或利用耐药演化。
查看英文原文 English abstract
Objective : We aimed to model the evolution of chemoresistance to methotrexate, doxorubicin, and cisplatin (MAP) in vitro and to characterize collateral drug sensitivity and resistance patterns over time, potentially informing second-line treatment strategies in chemo resistant primary or recurrent disease.
Methods : Five evolutionary replicates of MG63.3 osteosarcoma cells were treated with six complete cycles of pulsed, clinically relevant doses of cisplatin and doxorubicin, alternating with methotrexate. Dose-response curves were performed after each chemotherapy cycle to assess resistance to MAP and collateral responses to 16 drugs and combinations. RNA sequencing and transcription factor activity inference were performed across treatment timepoints to temporally explore transcriptional correlates of drug response.
Results : Cells developed resistance to doxorubicin (1.49-2.59 fold) and methotrexate (0.92-2.87 fold) but remained sensitive to cisplatin. Collateral resistance emerged to etoposide, vincristine, and topotecan, while sensitivity increased to gemcitabine, cabozantinib, and palifosfamide. Collateral responses varied temporally, with some increasing linearly with evolution of MAP resistance, and some appearing transient or stochastic. Transcriptional profiling revealed increased activity of E2F and ERG and context-dependent roles for interferon signaling. Resistance phenotypes persisted after drug withdrawal and cryopreservation.
Conclusion : Our model reveals temporally dynamic, heterogeneous collateral responses during the development of chemoresistance to MAP in osteosarcoma. While cross-resistance to several agents emerged, collateral sensitivity to gemcitabine and cabozantinib supports a second line use for these agents. These data may inform rational sequencing of therapies to preempt or exploit resistance evolution.
利益披露 Disclosure
E. Nowak, None..
J. Imamura, None.