The etiological role of NSD2 enzymatic activity in solid tumors is unclear. Here we show that NSD2, via H3K36me2 catalysis, cooperates with oncogenic KRAS signaling to drive lung adenocarcinoma (LUAD) pathogenesis. In vivo expression of NSD2_E1099K, a hyperactive variant detected in individuals with LUAD, rapidly accelerates malignant tumor progression while decreasing survival in KRAS-driven LUAD mouse models. Pathologic H3K36me2 generation by NSD2 amplifies transcriptional output of KRAS and several complementary oncogenic gene expression programs. We establish a versatile in vivo CRISPRi-based system to test gene functions in LUAD and find that NSD2 loss strongly attenuates tumor progression. NSD2 knockdown also blocks neoplastic growth of PDXs (patient-dervived xenografts) from primary LUAD. Finally, a treatment regimen combining NSD2 depletion with MEK1/2 inhibition causes nearly complete regression of LUAD tumors. Our work identifies NSD2 as a bona fide LUAD therapeutic target and suggests a pivotal epigenetic role of the NSD2-H3K36me2 axis in sustaining oncogenic signaling.

NSD2酶活性在实体瘤中的病因学作用尚不清楚。在这里，我们显示 NSD2 通过 H3K36me2 催化与致癌 KRAS 信号传导协同驱动肺腺癌 (LUAD) 发病机制。_{NSD2 E1099K的}体内表达是在 LUAD个体中检测到的一种过度活跃的变异体，它在 KRAS 驱动的 LUAD 小鼠模型中迅速加速恶性肿瘤进展，同时降低存活率。NSD2 产生的病理性 H3K36me2 放大了 KRAS 的转录输出和几个互补的致癌基因表达程序。我们建立了一个多功能的体内基于 CRISPRi 的系统用于测试 LUAD 中的基因功能，并发现 NSD2 缺失会强烈减弱肿瘤进展。NSD2 敲低还阻止了原发性 LUAD 的 PDX（患者衍生的异种移植物）的肿瘤生长。最后，将 NSD2 耗竭与 MEK1/2 抑制相结合的治疗方案导致 LUAD 肿瘤几乎完全消退。我们的工作将 NSD2 确定为真正的LUAD 治疗靶点，并表明 NSD2-H3K36me2 轴在维持致癌信号传导中的关键表观遗传作用。