ADAM9 deficiency mediates KRAS related pathways in pancreatic cancer cells. ADAM9 deficiency mediates KRAS related pathways in pancreatic cancer cells

Kirsten rat sarcoma virus (KRAS) signaling drives pancreatic ductal adenocarcinoma (PDAC) malignancy, which is an unmet clinical need. Here we identify a disintegrin and metalloproteinase domain 9 (ADAM9) as a modulator of PDAC progression via stabilization of wild-type and mutant KRAS proteins. Mechanistically, ADAM9 loss increases the interaction of KRAS with plasminogen activator inhibitor-1 (PAI-1), which functions as a selective autophagy receptor in conjunction with LC3, triggering the lysosomal degradation of KRAS. Suppression of ADAM9 by a small molecule inhibitor restricts disease progression in spontaneous models, and the combination with gemcitabine elicits dramatic regression of patient-derived tumors. Our findings provide a promising strategy to target the KRAS signaling cascade and demonstrate a potential modality to enhance sensitivity to chemotherapy in PDAC. Overall design: Comparative gene expression profiling analysis of RNA-seq data for Pan18 cells and its ADAM9 KO derivatives (ADAM9 WT and ADAM9 KO).

Kirsten大鼠肉瘤病毒（KRAS）信号通路驱动胰腺导管腺癌（PDAC）的恶性进展，该领域目前仍存在未被满足的临床需求。本研究鉴定出解整合素金属蛋白酶域9（ADAM9）可通过稳定野生型与突变型KRAS蛋白，调控胰腺导管腺癌的进程。机制层面，ADAM9缺失会增强KRAS与纤溶酶原激活物抑制剂-1（PAI-1）的相互作用；PAI-1可与微管相关蛋白1轻链3（LC3）协同作为选择性自噬受体，进而触发KRAS的溶酶体降解。采用小分子抑制剂抑制ADAM9，可限制自发肿瘤模型中的疾病进展；若联合吉西他滨（gemcitabine），则可显著诱导患者来源肿瘤的消退。本研究结果为靶向KRAS信号通路级联反应提供了极具前景的策略，并证实了一种可增强胰腺导管腺癌化疗敏感性的潜在手段。实验设计：对Pan18细胞及其ADAM9敲除衍生物（ADAM9 WT与ADAM9 KO）的RNA测序（RNA-seq）数据开展比较基因表达谱分析。