Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, Vic., Australia.
Department of Molecular and Translational Sciences, Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, Vic., Australia.
EMBO Mol Med. 2019 Apr;11(4). doi: 10.15252/emmm.201809976.
Oncogenic mutations are major drivers of lung adenocarcinoma (LAC), yet the direct therapeutic targeting of KRAS has been problematic. Here, we reveal an obligate requirement by oncogenic KRAS for the ADAM17 protease in LAC In genetically engineered and xenograft (human cell line and patient-derived) -driven LAC models, the specific blockade of ADAM17, including with a non-toxic prodomain inhibitor, suppressed tumor burden by reducing cellular proliferation. The pro-tumorigenic activity of ADAM17 was dependent upon its threonine phosphorylation by p38 MAPK, along with the preferential shedding of the ADAM17 substrate, IL-6R, to release soluble IL-6R that drives IL-6 trans-signaling via the ERK1/2 MAPK pathway. The requirement for ADAM17 in -driven LAC was independent of bone marrow-derived immune cells. Furthermore, in mutant human LAC, there was a significant positive correlation between augmented phospho-ADAM17 levels, observed primarily in epithelial rather than immune cells, and activation of ERK and p38 MAPK pathways. Collectively, these findings identify ADAM17 as a druggable target for oncogenic -driven LAC and provide the rationale to employ ADAM17-based therapeutic strategies for targeting mutant cancers.
致癌突变是肺腺癌（LAC）的主要驱动因素，但 KRAS 的直接治疗靶向一直存在问题。在这里，我们揭示了致癌 KRAS 在 LAC 中对 ADAM17 蛋白酶的强制性需求。在基因工程和异种移植（人细胞系和患者来源）驱动的 LAC 模型中，ADAM17 的特异性阻断，包括使用非毒性前导肽抑制剂，通过减少细胞增殖来抑制肿瘤负担。ADAM17 的促肿瘤活性依赖于其由 p38 MAPK 进行的苏氨酸磷酸化，以及 ADAM17 底物 IL-6R 的优先脱落，以释放可溶性 IL-6R，通过 ERK1/2 MAPK 途径驱动 IL-6 转信号。ADAM17 在 -驱动的 LAC 中的作用独立于骨髓来源的免疫细胞。此外，在 突变的人类 LAC 中，观察到的磷酸化 ADAM17 水平增加与 ERK 和 p38 MAPK 途径的激活之间存在显著的正相关，主要发生在上皮细胞而不是免疫细胞中。总的来说，这些发现将 ADAM17 鉴定为一种可用于治疗致癌驱动的 LAC 的药物靶点，并为使用基于 ADAM17 的治疗策略靶向 突变癌症提供了依据。
