Brew Tom, Bougen-Zhukov Nicola, Mitchell Wilson, Decourtye Lyvianne, Schulpen Emily, Nouri Yasmin, Godwin Tanis, Guilford Parry
Cancer Genetics Laboratory, Centre for Translational Cancer Research (Te Aho Matatū), Department of Biochemistry, University of Otago, Dunedin 9016, New Zealand.
Cancers (Basel). 2021 Dec 26;14(1):102. doi: 10.3390/cancers14010102.
Germline inactivating variants of are causative of hereditary diffuse gastric cancer (HDGC), a cancer syndrome characterized by an increased risk of both diffuse gastric cancer and lobular breast cancer. Because loss of function mutations are difficult to target therapeutically, we have taken a synthetic lethal approach to identify targetable vulnerabilities in -null cells. We have previously observed that -null MCF10A cells exhibit a reduced rate of endocytosis relative to wildtype MCF10A cells. To determine whether this deficiency is associated with wider vulnerabilities in vesicle trafficking, we screened isogenic MCF10A cell lines with known inhibitors of autophagy, endocytosis, and sphingolipid metabolism. Relative to wildtype MCF10A cells, MCF10A cells showed significantly greater sensitivity to several drugs targeting these processes, including the autophagy inhibitor chloroquine, the endocytosis inhibitors chlorpromazine and PP1, and the sphingosine kinase 1 inhibitor PF-543. Synthetic lethality was confirmed in both gastric and mammary organoid models of loss, derived from -Cre//tdTomato mice. Collectively, these results suggest that both sphingolipid metabolism and vesicle trafficking represent previously unrecognised druggable vulnerabilities in -null cells and may lead to the development of new therapies for HDGC.
[基因名称]的种系失活变体是遗传性弥漫性胃癌（HDGC）的病因，HDGC是一种癌症综合征，其特征是弥漫性胃癌和小叶乳腺癌的发病风险增加。由于功能丧失突变难以成为治疗靶点，我们采用了合成致死方法来确定[基因名称]缺失细胞中可靶向的脆弱性。我们之前观察到，[基因名称]缺失的MCF10A细胞相对于野生型MCF10A细胞，其胞吞作用速率降低。为了确定这种缺陷是否与囊泡运输中更广泛的脆弱性相关，我们用自噬、胞吞作用和鞘脂代谢的已知抑制剂筛选了同基因MCF10A细胞系。相对于野生型MCF10A细胞，[基因名称]缺失的MCF10A细胞对几种靶向这些过程的药物表现出显著更高的敏感性，包括自噬抑制剂氯喹、胞吞作用抑制剂氯丙嗪和PP1，以及鞘氨醇激酶1抑制剂PF-543。在源自[基因名称]-Cre//tdTomato小鼠的[基因名称]缺失的胃和乳腺类器官模型中证实了合成致死性。总体而言，这些结果表明鞘脂代谢和囊泡运输在[基因名称]缺失的细胞中均代表了以前未被认识到的可药物化的脆弱性，并可能导致HDGC新疗法的开发。
