Therapeutic efficacy of ABT-737, a selective inhibitor of BCL-2, in small cell lung cancer
Therapeutic efficacy of ABT-737, a selective inhibitor of BCL-2, in small cell lung cancer
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DOI：
10.1158/0008-5472.can-07-5031
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发表时间：
2008-04-01
期刊：
影响因子：
11.2
通讯作者：
Rudin, Charles M.
中科院分区：
文献类型：
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作者：
Hann, Christine L.;Daniel, Vincent C.;Rudin, Charles M.
Bcl-2是细胞存活的中心调节因子，在大多数小细胞肺癌（SCLC）中过度表达，并有助于恶性转化和治疗耐药性。我们比较了从新生的人类肿瘤中制备的原发性SCLC异种移植物与基于标准细胞系的异种移植物，以评估一种新型高效的Bcl-2小分子抑制剂ABT-737。ABT-737在一些SCLC细胞系衍生的肿瘤中诱导了显著的退化。相比之下，三种原发异种移植SCLC肿瘤中只有一种用ABT-737表现出明显的生长抑制。对这种明显的二分法的解释可能包括原发异种移植物中相对较低的Bcl-2表达或模型系统的固有差异。在原发性异种移植物ABT-737中添加依托泊苷可显著降低肿瘤生长，强调ABT-737联合治疗的临床潜力。为了确定可能导致ABT-737和相关抑制剂耐药的因素，我们分离了一种最初敏感的细胞系异种移植物的耐药衍生物。在该模型中，获得性耐药与主要靶点Bcl-2、Bcl-2的促凋亡伴侣（Bax和Bim）以及Bcl-2:Bim异源二聚体的表达降低有关。表达谱显示85个候选基因表现出与获得性耐药一致的基因表达变化。综上所述，这些数据对SCLC Bcl-2抑制剂的临床开发具有特殊意义，对相关临床前模型中新型抗癌策略的测试具有更广泛的意义。
Bcl-2 is a central regulator of cell survival that is overexpressed in the majority of small cell lung cancers (SCLC) and contributes to both malignant transformation and therapeutic resistance. We compared primary SCLC xenografts prepared from de novo human tumors with standard cell line-based xenografts in the evaluation of a novel and highly potent small molecule inhibitor of Bcl-2, ABT-737. ABT-737 induced dramatic regressions in tumors derived from some SCLC cell lines. In contrast, only one of three primary xenograft SCLC tumors showed significant growth inhibition with ABT-737. Explanations for this apparent dichotomy may include relatively low expression of Bcl-2 in the primary xenografts or inherent differences in the model systems. The addition of etoposide to ABT-737 in the primary xenografts resulted in significant decreases in tumor growth, underscoring the clinical potential of ABT-737 in combination therapy. To identify factors that may contribute to resistance to ABT-737 and related inhibitors, we isolated resistant derivatives of an initially sensitive cell line-based xenograft. Acquired resistance in this model was associated with decreases in the expression of the primary target Bcl-2, of proapoptotic partners of Bcl-2 (Bax and Bim), and of Bcl-2:Bim heterodimers. Expression profiling reveals 85 candidate genes demonstrating consistent changes in gene expression with acquired resistance. Taken together, these data have specific implications for the clinical development of Bcl-2 inhibitors for SCLC and broader implications for the testing of novel anticancer strategies in relevant preclinical models.