Assessment of ABT-263 activity across a cancer cell line collection leads to a potent combination therapy for small-cell lung cancer
Assessment of ABT-263 activity across a cancer cell line collection leads to a potent combination therapy for small-cell lung cancer
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DOI：
10.1073/pnas.1411848112
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发表时间：
2015-03-17
影响因子：
11.1
通讯作者：
Engelman, Jeffrey A.
中科院分区：
文献类型：
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作者：
Faber, Anthony C.;Farago, Anna F.;Engelman, Jeffrey A.
BH 3模拟物如ABT-263在癌症模型的子集中诱导细胞凋亡。然而，这些药物作为单一药物在小细胞肺癌（SCLC）和其他实体瘤恶性肿瘤中显示出有限的临床疗效，合理的联合策略仍有待探索。为了开发一种新的治疗方法，我们检查了ABT-263在超过500种癌细胞系中的疗效，其中包括311种我们有选择基因的匹配表达数据。我们发现，高表达的促凋亡基因Bcl-2相互作用的细胞死亡（BIM）介导预测ABT-263的敏感性。特别是，SCLC细胞系具有比大多数其他实体瘤更高的BIM转录水平，并且是对ABT-263最敏感的细胞系之一。然而，相对耐药的SCLC细胞系的子集具有抗凋亡骨髓细胞白血病1（MCL-1）的伴随高表达。而ABT-263从与BCL-2和BCL-XL的复合物中释放BIM，MCL-1的高表达螯合了从BCL-2和BCL-XL释放的BIM，从而消除了凋亡。我们发现SCLC通过TORC 1/2抑制对ABT-263敏感，这导致MCL-1蛋白水平降低，从而促进BIM介导的凋亡。AZD 8055和ABT-263在体外共同诱导显著的细胞凋亡，以及在多种SCLC异种移植模型中的肿瘤消退。在TP 53中; Rb 1缺失基因工程小鼠SCLC模型中，ABT-263和AZD 8055联合用药与单独用药相比，可显著抑制肿瘤生长并诱导肿瘤消退。此外，在对ABT-263单独耐药的SCLC患者来源的异种移植模型中，添加AZD 8055诱导了有效的肿瘤消退。因此，添加TORC 1/2抑制剂提供了一种治疗策略，以显着提高ABT-263在SCLC中的活性。
BH3 mimetics such as ABT-263 induce apoptosis in a subset of cancer models. However, these drugs have shown limited clinical efficacy as single agents in small-cell lung cancer (SCLC) and other solid tumor malignancies, and rational combination strategies remain underexplored. To develop a novel therapeutic approach, we examined the efficacy of ABT-263 across > 500 cancer cell lines, including 311 for which we had matched expression data for select genes. We found that high expression of the proapoptotic gene Bcl2-interacting mediator of cell death (BIM) predicts sensitivity to ABT-263. In particular, SCLC cell lines possessed greater BIM transcript levels than most other solid tumors and are among the most sensitive to ABT-263. However, a subset of relatively resistant SCLC cell lines has concomitant high expression of the antiapoptotic myeloid cell leukemia 1 (MCL-1). Whereas ABT-263 released BIM from complexes with BCL-2 and BCL-XL, high expression of MCL-1 sequestered BIM released from BCL-2 and BCL-XL, thereby abrogating apoptosis. We found that SCLCs were sensitized to ABT-263 via TORC1/2 inhibition, which led to reduced MCL-1 protein levels, thereby facilitating BIM-mediated apoptosis. AZD8055 and ABT-263 together induced marked apoptosis in vitro, as well as tumor regressions in multiple SCLC xenograft models. In a Tp53; Rb1 deletion genetically engineered mouse model of SCLC, the combination of ABT-263 and AZD8055 significantly repressed tumor growth and induced tumor regressions compared with either drug alone. Furthermore, in a SCLC patient-derived xenograft model that was resistant to ABT-263 alone, the addition of AZD8055 induced potent tumor regression. Therefore, addition of a TORC1/2 inhibitor offers a therapeutic strategy to markedly improve ABT-263 activity in SCLC.