Authors' Affiliations: Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine; Departments of Oncology and Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, Maryland; and Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New YorkAuthors' Affiliations: Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine; Departments of Oncology and Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, Maryland; and Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York.
Authors' Affiliations: Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine; Departments of Oncology and Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, Maryland; and Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York.
Cancer Res. 2014 May 15;74(10):2846-56. doi: 10.1158/0008-5472.CAN-13-3460. Epub 2014 Mar 10.
Overexpression of the antiapoptotic protein Bcl-2 is observed in the majority of small cell lung cancer (SCLC) cases and is associated with resistance to chemotherapy. While targeting Bcl-2 in hematologic malignancies continues to show signs of promise, translating the BH3 mimetic ABT-737 (or ABT-263; navitoclax) to the clinic for solid tumors has remained problematic, with limited single-agent activity in early-phase clinical trials. Here, we used patient-derived xenograft (PDX) models of SCLC to study ABT-737 resistance and demonstrated that responses to ABT-737 are short lived and coincide with decreases in HIF-1α-regulated transcripts. Combining the mTOR inhibitor rapamycin with ABT-737 rescued this resistance mechanism, was highly synergistic in vitro, and provided durable tumor regressions in vivo without notable hematologic suppression. In comparison, tumor regressions did not occur when ABT-737 was combined with etoposide, a gold-standard cytotoxic for SCLC therapy. Rapamycin exposure was consistently associated with an increase in the proapoptotic protein BAX, whereas ABT-737 caused dose-dependent decreases in BAX. As ABT-737 triggers programmed cell death in a BAX/BAK-dependent manner, we provide preclinical evidence that the efficacy of ABT-737 as a single agent is self-limiting in SCLC, but the addition of rapamycin can maintain or increase levels of BAX protein and markedly enhance the anticancer efficacy of ABT-737. These data have direct translational implications for SCLC clinical trials.
抗凋亡蛋白 Bcl-2 的过度表达在大多数小细胞肺癌 (SCLC) 病例中都有观察到，并且与化疗耐药有关。虽然针对血液恶性肿瘤中的 Bcl-2 的靶向治疗继续显示出有前景的迹象，但将 BH3 模拟物 ABT-737（或 ABT-263；navitoclax）转化为实体瘤的临床应用仍然存在问题，在早期临床试验中，单一药物的活性有限。在这里，我们使用 SCLC 的患者来源异种移植 (PDX) 模型来研究 ABT-737 耐药性，并证明对 ABT-737 的反应是短暂的，并且与 HIF-1α 调节的转录物减少相吻合。将 mTOR 抑制剂 rapamycin 与 ABT-737 联合使用可以挽救这种耐药机制，在体外具有高度协同作用，并在体内提供持久的肿瘤消退而没有明显的血液学抑制。相比之下，当 ABT-737 与依托泊苷联合使用时，肿瘤并没有消退，依托泊苷是 SCLC 治疗的金标准细胞毒性药物。Rapamycin 暴露始终与促凋亡蛋白 BAX 的增加相关，而 ABT-737 导致 BAX 剂量依赖性减少。由于 ABT-737 以 BAX/BAK 依赖的方式触发程序性细胞死亡，因此我们提供了临床前证据表明，ABT-737 作为单一药物在 SCLC 中的疗效是自我限制的，但是添加 rapamycin 可以维持或增加 BAX 蛋白的水平，并显著增强 ABT-737 的抗癌疗效。这些数据对 SCLC 临床试验具有直接的转化意义。
