Algoma District Cancer Program, Sault Area Hospital, Sault Ste. Marie, Ontario, Canada; Section of Internal Medicine, Division of Clinical Sciences, Northern Ontario School of Medicine, Sudbury, Ontario, Canada.
Gene. 2022 Dec 30;847:146881. doi: 10.1016/j.gene.2022.146881. Epub 2022 Sep 11.
Breast cancer is one of the most prevalent cancers and a cause of significant morbidity and mortality. Despite introduction of new therapies that improve control of the disease, metastatic breast cancer remains still incurable in most cases. Further therapies based on a better understanding of the pathogenesis of breast cancers and its sub-types are needed to improve outcomes. Apoptosis has arisen as a potential target in recent years. Research on therapeutic use of apoptosis promoting drugs could be advanced by cell line models of efficacy.
Alterations in antiapoptotic members of the BCL2 family of proteins encoded by genes BCL2, BCL2L1, BCL2L2, MCL1 and BCL2A1 were evaluated in breast cancer cell lines from the Cancer Cell Line Encyclopedia (CCLE). Sensitivities of breast cancer cell lines to apoptosis promoting drugs were evaluated using the Genomics of Drug Sensitivity in Cancer (GDSC) platform. Concomitant molecular aberrations of sensitive and resistant cell lines were examined for recurrent themes. Cell line dependencies were surveyed using publicly available CRISPR and RNAi arrays.
Breast cancer cell lines, in concordance with breast cancer patient samples, commonly exhibit amplifications in the BCL2 member MCL1 but not other molecular alterations in antiapoptotic family members. The panel of breast cancer cell lines with sensitivity to drugs inhibiting MCL1, with or without inhibition of other family members consists exclusively of cell lines of the basal phenotype. Sensitive cell lines possess fewer amplifications in the commonly amplified in breast cancer loci at 8q23, 11q13, 17q12 and 1q21. Dependency analysis suggests that in some instances activity of cancer related pathways such as PI3K/ AKT and WNT/ β-catenin may affect apoptosis threshold.
Breast cancer cell line models faithfully depict the most common molecular aberration in BCL2 family proteins observed in clinical breast cancer samples, MCL1 amplifications. Basal cell lines may be a preferred target of MCL1 inhibitors. However, concomitant aberrations, as explored in this report, are likely to be involved in ultimate sensitivity to anti-apoptosis targeting therapies.
乳腺癌是最常见的癌症之一，也是导致高发病率和死亡率的主要原因之一。尽管引入了新的治疗方法来改善疾病的控制，但在大多数情况下，转移性乳腺癌仍然无法治愈。需要进一步基于对乳腺癌及其亚型发病机制的更好理解的治疗方法来改善治疗效果。近年来，细胞凋亡已成为一个潜在的治疗靶点。通过细胞系模型研究促进细胞凋亡的药物的治疗用途，可以推进相关研究。
在癌症细胞系百科全书（Cancer Cell Line Encyclopedia，CCLE）中评估了由 BCL2、BCL2L1、BCL2L2、MCL1 和 BCL2A1 基因编码的 BCL2 家族抗凋亡蛋白的改变。使用癌症药物基因组学敏感性（Genomics of Drug Sensitivity in Cancer，GDSC）平台评估乳腺癌细胞系对促进细胞凋亡药物的敏感性。同时，检查敏感和耐药细胞系的分子异常，以寻找常见的主题。使用公共的 CRISPR 和 RNAi 阵列调查细胞系的依赖性。
乳腺癌细胞系与乳腺癌患者样本一致，常见的分子改变是 MCL1 的扩增，而不是抗凋亡家族成员的其他分子改变。对 MCL1 抑制剂敏感的乳腺癌细胞系药物的细胞系面板，无论是单独抑制 MCL1 还是同时抑制其他家族成员，都仅由基底表型的细胞系组成。敏感细胞系在乳腺癌中常见扩增的染色体区域 8q23、11q13、17q12 和 1q21 上的扩增较少。依赖性分析表明，在某些情况下，癌症相关通路（如 PI3K/AKT 和 WNT/β-catenin）的活性可能会影响细胞凋亡的阈值。
乳腺癌细胞系模型忠实地描绘了在临床乳腺癌样本中观察到的 BCL2 家族蛋白最常见的分子改变，即 MCL1 扩增。基底细胞系可能是 MCL1 抑制剂的首选靶点。然而，如本报告所述，伴随的异常可能与对细胞凋亡靶向治疗的最终敏感性有关。
