治疗诱导的瘤分泌物促进抵抗和瘤的进展
Anna C Obenauf1, Yilong Zou2, Andrew L Ji1
1Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.
Nature
|March 26, 2015
概括
有针对性的癌症治疗可以通过分泌的信号,矛盾地促进耐药细胞的生长. 针对RAF和PI3K/AKT/mTOR途径的组合疗法可以克服这种抵抗并防止瘤复发.
科学领域:
- 在瘤学瘤学.
- 分子生物学分子生物学
- 癌症研究 癌症研究
背景情况:
- 药物耐药性限制了向激酶抑制剂在癌症中的有效性.
- 向治疗可以在癌细胞中诱导复杂的信号网络.
研究的目的:
- 研究激酶抑制剂对癌细胞分泌物的影响.
- 确定治疗诱导的分泌体如何影响耐药和敏感的癌细胞.
- 确定克服药物耐药性的治疗策略.
主要方法:
- 用激酶抑制剂 (BRAF,ALK,EGFR) 治疗人类和小鼠黑色素瘤和肺腺癌细胞.
- 对药物压力癌细胞产生的分泌体的分析.
- 在现场对耐药黑色素瘤细胞的转录组分析.
- 针对RAF和PI3K/AKT/mTOR通路的组合疗法的评估.
主要成果:
- 激酶抑制剂诱导一种促进瘤的分泌物,该分泌物支持耐药克隆的扩张和转移.
- 黑色素瘤中Vemurafenib诱导的分泌是由FRA1下调驱动的.
- 耐药黑色素瘤细胞显示AKT通路过活化.
- RAF和PI3K/AKT/mTOR抑制剂的联合治疗减少了BRAF突变黑色素瘤中耐药细胞的生长.
结论:
- 治疗性抑制瘤驱动因素会改变癌细胞的秘密体,从而创造出一种亲瘤的微环境.
- 这种微环境矛盾地支持耐药克隆的扩张.
- 针对关键信号通路的组合疗法提供了一种打击瘤复发和抵抗的策略.
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