Mondal Priya, Alyateem George, Mitchell Allison V, Gottesman Michael M
Laboratory of Cell Biology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892.
bioRxiv. 2024 Feb 15:2024.02.15.580539. doi: 10.1101/2024.02.15.580539.
Pancreatic adenocarcinoma is one of the most aggressive and lethal forms of cancer. Chemotherapy is the primary treatment for pancreatic cancer, but resistance to the drugs used remains a major challenge. A genome-wide CRISPR interference and knockout screen in the PANC-1 cell line with the drug nab-paclitaxel has identified a group of spindle assembly checkpoint (SAC) genes that enhance survival in nab-paclitaxel. Knockdown of these SAC genes (BUB1B, BUB3, and TTK) attenuates paclitaxel-induced cell death. Cells treated with the small molecule inhibitors BAY 1217389 or MPI 0479605, targeting the threonine tyrosine kinase (TTK), also enhance survival in paclitaxel. Overexpression of these SAC genes does not affect sensitivity to paclitaxel. These discoveries have helped to elucidate the mechanisms behind paclitaxel cytotoxicity. The outcomes of this investigation may pave the way for a deeper comprehension of the diverse responses of pancreatic cancer to therapies including paclitaxel. Additionally, they could facilitate the formulation of novel treatment approaches for pancreatic cancer.
胰腺腺癌是最具侵袭性和致命性的癌症形式之一。化疗是胰腺癌的主要治疗方法，但对所用药物产生耐药性仍然是一个重大挑战。在PANC - 1细胞系中使用纳米白蛋白结合型紫杉醇进行全基因组CRISPR干扰和敲除筛选，已鉴定出一组纺锤体组装检查点（SAC）基因，这些基因可提高细胞在纳米白蛋白结合型紫杉醇中的存活率。敲低这些SAC基因（BUB1B、BUB3和TTK）可减弱紫杉醇诱导的细胞死亡。用靶向苏氨酸酪氨酸激酶（TTK）的小分子抑制剂BAY 1217389或MPI 0479605处理细胞，也可提高细胞在紫杉醇中的存活率。这些SAC基因的过表达并不影响细胞对紫杉醇的敏感性。这些发现有助于阐明紫杉醇细胞毒性背后的机制。这项研究的结果可能为更深入理解胰腺癌对包括紫杉醇在内的治疗的不同反应铺平道路。此外，它们还可能促进胰腺癌新治疗方法的制定。
