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 (ADAM)9 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 light chain 3 (LC3), triggering lysosomal degradation of KRAS. Suppression of ADAM9 by a small-molecule inhibitor restricts disease progression in spontaneous models, and 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.

克尔斯滕大鼠肉瘤病毒（KRAS）信号传导导致胰腺导管腺癌（PDAC）恶性肿瘤，这是一个未满足的临床需求。在这里，我们通过稳定野生型和突变型 KRAS 蛋白，确定了解整合素和金属蛋白酶结构域 (ADAM)9 作为 PDAC 进展的调节剂。从机制上讲，ADAM9 缺失会增加 KRAS 与纤溶酶原激活剂抑制剂 1 (PAI-1) 的相互作用，后者与轻链 3 (LC3) 一起作为选择性自噬受体，触发 KRAS 的溶酶体降解。小分子抑制剂抑制 ADAM9 可限制自发模型中的疾病进展，与吉西他滨联合可引起患者源性肿瘤的显着消退。我们的研究结果提供了一种有前景的策略来靶向 KRAS 信号级联，并证明了增强 PDAC 对化疗敏感性的潜在方式。