EGFR-RAS-ERK 通路是细胞存活、生长和增殖中最重要的信号级联反应之一。该通路的异常激活是各种癌症的常见机制。在此，我们报告 CDK2 是通过 USP37 去泛素酶 (DUB) 调节 ERK 通路的新型调节剂。从机制上讲，CDK2 磷酸化 USP37，这是 USP37 DUB 活性所必需的。此外，USP37 去泛素化并稳定 ERK1/2，从而增强癌细胞增殖。因此，CDK2 能够通过激活 USP37 促进细胞增殖，进而稳定 ERK1/2。重要的是，CDK1/2 和 EGFR 抑制剂组合通过下调 ERK1/2 稳定性和活性具有协同抗癌作用。事实上，我们的患者来源的异种移植（PDX）结果表明，即使在这两种抑制剂剂量较低的情况下，同时靶向 ERK1/2 稳定性和活性也能更有效地杀死癌细胞，这可能会减少它们相关的副作用，并表明一种潜在的新组合策略癌症治疗。© 2023 Wu 等人。

The EGFR-RAS-ERK pathway is one of the most important signaling cascades in cell survival, growth, and proliferation. Aberrant activation of this pathway is a common mechanism in various cancers. Here, we report that CDK2 is a novel regulator of the ERK pathway via USP37 deubiquitinase (DUB). Mechanistically, CDK2 phosphorylates USP37, which is required for USP37 DUB activity. Further, USP37 deubiquitinates and stabilizes ERK1/2, thereby enhancing cancer cell proliferation. Thus, CDK2 is able to promote cell proliferation by activating USP37 and, in turn, stabilizing ERK1/2. Importantly, combined CDK1/2 and EGFR inhibitors have a synergetic anticancer effect through the downregulation of ERK1/2 stability and activity. Indeed, our patient-derived xenograft (PDX) results suggest that targeting both ERK1/2 stability and activity kills cancer cells more efficiently even at lower doses of these two inhibitors, which may reduce their associated side effects and indicate a potential new combination strategy for cancer therapy.© 2023 Wu et al.