Barts Cancer Institute, Queen Mary University of London, John Vane Science Centre, Charterhouse Square, London, EC1M6 BQ, UK.
York Biomedical Research Institute, University of York, Wentworth Way, York, YO10 5DD, UK.
Cell Death Dis. 2021 Nov 11;12(11):1075. doi: 10.1038/s41419-021-04355-7.
An early event in lung oncogenesis is loss of the tumour suppressor gene LIMD1 (LIM domains containing 1); this encodes a scaffold protein, which suppresses tumorigenesis via a number of different mechanisms. Approximately 45% of non-small cell lung cancers (NSCLC) are deficient in LIMD1, yet this subtype of NSCLC has been overlooked in preclinical and clinical investigations. Defining therapeutic targets in these LIMD1 loss-of-function patients is difficult due to a lack of 'druggable' targets, thus alternative approaches are required. To this end, we performed the first drug repurposing screen to identify compounds that confer synthetic lethality with LIMD1 loss in NSCLC cells. PF-477736 was shown to selectively target LIMD1-deficient cells in vitro through inhibition of multiple kinases, inducing cell death via apoptosis. Furthermore, PF-477736 was effective in treating LIMD1 tumours in subcutaneous xenograft models, with no significant effect in LIMD1 cells. We have identified a novel drug tool with significant preclinical characterisation that serves as an excellent candidate to explore and define LIMD1-deficient cancers as a new therapeutic subgroup of critical unmet need.
肺肿瘤发生的早期事件是抑癌基因 LIMD1（含 LIM 结构域蛋白 1）的缺失；该基因编码支架蛋白，通过多种不同机制抑制肿瘤发生。大约 45%的非小细胞肺癌（NSCLC）存在 LIMD1 缺失，但这种 NSCLC 亚型在临床前和临床研究中被忽视。由于缺乏“可用药”靶点，因此很难在这些 LIMD1 功能丧失型患者中定义治疗靶点，需要采用替代方法。为此，我们进行了首次药物重定位筛选，以确定在 NSCLC 细胞中与 LIMD1 缺失具有合成致死性的化合物。PF-477736 通过抑制多种激酶选择性地靶向 LIMD1 缺失细胞，通过细胞凋亡诱导细胞死亡。此外，PF-477736 在 LIMD1 肿瘤的皮下异种移植模型中具有疗效，而在 LIMD1 细胞中无明显作用。我们已经确定了一种具有显著临床前特征的新型药物工具，可作为探索和定义 LIMD1 缺失癌症作为新的治疗亚组的重要未满足需求的优秀候选药物。
