Department of Medical Oncology, National Center for Tumor Diseases (NCT), University Hospital Heidelberg, 69120, Heidelberg, Germany.
Department of Translational Medical Oncology, National Center for Tumor Diseases (NCT) Heidelberg, German Cancer Research Center (DKFZ), 69120, Heidelberg, Germany.
Cell Death Dis. 2020 Oct 17;11(10):875. doi: 10.1038/s41419-020-03092-7.
Since metastatic colorectal cancer (CRC) is a leading cause of cancer-related death, therapeutic approaches overcoming primary and acquired therapy resistance are an urgent medical need. In this study, the efficacy and toxicity of high-affinity inhibitors targeting antiapoptotic BCL-2 proteins (BCL-2, BCL-XL, and MCL-1) were evaluated. By RNA sequencing analysis of a pan-cancer cohort comprising >1500 patients and subsequent prediction of protein activity, BCL-XL was identified as the only antiapoptotic BCL-2 protein that is overactivated in CRC. Consistently, pharmacologic and genetic inhibition of BCL-XL induced apoptosis in human CRC cell lines. In a combined treatment approach, targeting BCL-XL augmented the efficacy of chemotherapy in vitro, in a murine CRC model, and in human ex vivo derived CRC tissue cultures. Collectively, these data show that targeting of BCL-XL is efficient and safe in preclinical CRC models, observations that pave the way for clinical translation.
由于转移性结直肠癌 (CRC) 是癌症相关死亡的主要原因，因此克服原发性和获得性治疗耐药性的治疗方法是迫切的医疗需求。在这项研究中，评估了针对抗凋亡 BCL-2 蛋白（BCL-2、BCL-XL 和 MCL-1）的高亲和力抑制剂的疗效和毒性。通过对包含 >1500 名患者的泛癌队列进行 RNA 测序分析，并随后预测蛋白质活性，鉴定出 BCL-XL 是唯一在 CRC 中过度激活的抗凋亡 BCL-2 蛋白。一致地，BCL-XL 的药理学和遗传学抑制诱导了人 CRC 细胞系的凋亡。在联合治疗方法中，靶向 BCL-XL 增强了体外、在鼠 CRC 模型中和在人离体衍生的 CRC 组织培养物中的化疗疗效。总之，这些数据表明，在临床前 CRC 模型中靶向 BCL-XL 是有效且安全的，为临床转化铺平了道路。
