New compounds triggering endoplasmic reticulum stress exert anti-melanoma effects and overcome BRAF inhibitor resistance. Homo sapiens

We discovered and developed a new series of molecules (thiazole benzenesulfonamides). HA15, the lead compound of this series, displayed anti-cancerous activity on all tested melanoma cells including those isolated from patients and those that developed resistance to BRAF inhibitors. Our molecule displayed activity against other liquid and solid tumors. HA15 also exhibited strong efficacy in xenograft mouse models with melanoma cells either sensitive or resistant to BRAF inhibitors. Transcriptomic, proteomic and biochemical studies identified the chaperone BiP/GRP78/HSPA5 as the specific target of HA15 and demonstrated that the interaction increases endoplasmic reticulum (ER) stress, leading to melanoma cell death by concomitant induction of autophagic and apoptotic mechanisms. Overall design: Profiling of 3 human melanoma cell lines (SKMel28, Mel501, A375) treated with HA15 at 10 uM or with DMSO was performed using whole genome human microarrays. Cells were incubated with DMSO or HA15 for 6h and then lysed prior to RNA isolation, labelling and hybridization on microarrays. One color experiment, total of 6 samples.

本研究发现并开发了一类新型噻唑苯磺酰胺类（thiazole benzenesulfonamides）分子。该系列的先导化合物HA15对所有受试黑色素瘤细胞均展现出抗肿瘤活性，涵盖从患者体内分离的细胞以及对BRAF抑制剂产生耐药性的细胞。本研究开发的分子对其他实体瘤与液体瘤均具有抗肿瘤活性。在携带对BRAF抑制剂敏感或耐药的黑色素瘤细胞的异种移植小鼠模型中，HA15也表现出显著的治疗效果。转录组学、蛋白质组学与生物化学研究确定，分子伴侣BiP/GRP78/HSPA5是HA15的特异性作用靶点，并证实二者的结合会加剧内质网（ER）应激，通过同时诱导自噬与凋亡通路导致黑色素瘤细胞死亡。整体实验设计：采用全基因组人类微阵列，对用10 μM HA15或二甲基亚砜（DMSO）处理的3株人类黑色素瘤细胞系（SKMel28、Mel501、A375）进行转录谱分析。细胞经DMSO或HA15孵育6小时后裂解，随后进行RNA提取、标记并在微阵列上杂交。本实验为单通道检测，共计6份样本。