Cyclin-dependent kinase (CDK) 4/6 inhibition in non-small cell lung cancer with epidermal growth factor receptor (EGFR) mutations
Cyclin-dependent kinase (CDK) 4/6 inhibition in non-small cell lung cancer with epidermal growth factor receptor (EGFR) mutations
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DOI：
10.1007/s10637-023-01337-8
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发表时间：
2023-02-15
影响因子：
3.4
通讯作者：
Sugio，Kenji
中科院分区：
文献类型：
--
作者：
Osoegawa，Atsushi;Takumi，Yohei;Sugio，Kenji
背景肺癌是世界范围内最主要的癌症死亡原因，而EGFR突变是亚洲肺腺癌患者最常见的基因改变。虽然奥西美替尼已被证明对携带EGFR突变的肺癌患者有效，但大多数患者最终会对治疗产生获得性耐药性。我们探讨了细胞周期蛋白D1在 = 突变患者中表达的意义，以及在体外联合应用细胞周期蛋白依赖性激酶4/6抑制剂阿贝米库和奥西美替尼的潜在疗效。材料与方法应用抗细胞周期蛋白D1抗体对83例 = 突变患者(男性，n EGFR 27；pStage 0-I，n EGFR 71)进行免疫组织化学染色，分析其表达与临床病理因素的关系。结果18.1%的 ≥ 基因突变患者细胞周期蛋白D1呈阴性表达，且与pStage = Ⅱ(p = 0.001.0 2)、淋巴结转移(p = 0.0 1)和淋巴转移(p EGFR 0.0 1)密切相关。细胞周期蛋白D1阴性组的无复发生存期显著缩短(p = 0.02)，尽管这种差异在限于pN0患者时消失。在EGFR突变的细胞株中，奥西美替尼和阿贝西利联合应用可能通过抑制AKT的磷酸化而发挥协同作用。结论CDK4/6抑制剂和EGFR-TKI联合治疗可能是一种有前景的治疗方法。
BackgroundLung cancer is the leading cause of cancer death worldwide, andEGFRmutation is the most common genetic alteration among Asian patients with lung adenocarcinoma. While osimertinib has been shown to be effective in lung cancer patients withEGFRmutation, the majority of patients eventually develop acquired resistance to treatment. We explored the significance of the cyclin D1 expression in patients withEGFRmutation and the potential efficacy of adding abemaciclib, a cyclin-dependent kinase (CDK) 4/6 inhibitor, simultaneously with osimertinib in vitro.Materials and methodsImmunohistochemical staining, using an anti-cyclin D1 antibody, of specimens from 83 patients withEGFRmutation (male, n = 27; pStage 0-I, n = 71) who were treated by surgical resection between 2017 and 2020, and the relationship between the cyclin D1 expression and clinicopathological factors was analyzed. Additionally, the combined effect of osimertinib and abemaciclib in lung cancer cell lines were analyzed using a growth inhibition test, and the signaling pathway underlying the combined effect was investigated.ResultsCyclin D1 was negative in 18.1% of patients withEGFRmutation, and cyclin D1 negativity was associated with pStage ≥ II (p = 0.02), lymph node metastasis (p = 0.001), and lymphatic invasion (p = 0.01). The cyclin D1-negative group had significantly shorter recurrence-free survival (p = 0.02), although this difference disappeared when limited to pN0 patients. InEGFRmutated cell lines, the combination of osimertinib and abemaciclib demonstrated synergistic effects, which were thought to be mediated by the inhibition of AKT phosphorylation.ConclusionCombination therapy with CDK4/6 inhibitors and EGFR-TKIs may be a promising approach.