Purpose: Osimertinib is an epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) indicated for the treatment of EGFR mutated (EGFRm)-driven lung adenocarcinomas. Osimertinib significantly improves progression-free survival in first-line treated patients with EGFRm advanced NSCLC. Despite the durable disease control, the majority of patients receiving osimertinib eventually develop disease progression. Experimental Design: ctDNA profiling analysis on-progression plasma samples from patients treated with osimertinib in both first (Phase 3, FLAURA trial) and second-line trials (Phase 3, AURA3 trial) revealed a high prevalence of PIK3CA/AKT/PTEN alterations. In vitro and in vivo evidence using CRISPR engineered NSCLC cell lines and PXD models support a functional role for PIK3CA and PTEN mutations in the development of osimertinib resistance. Results: These alterations are functionally relevant as EGFRm NSCLC cells with engineered PIK3CA/AKT/PTEN alterations develop resistance to osimertinib and can be re-sensitized by treatment with the combination of osimertinib and the AKT inhibitor capivasertib. Moreover, xenograft and PDX in vivo models with PIK3CA/AKT/PTEN alterations display limited sensitivity to osimertinib relative to models without alteration, and in these double mutant models capivasertib and osimertinib combination elicits an improved anti-tumor effect versus osimertinib alone. Conclusions: Together, this approach offers a potential treatment strategy for patients with EGFRm-driven NSCLC that have a sub-optimal response, or develop resistance, to osimertinib through PIK3CA/AKT/PTEN alterations.

中文翻译：

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在 EGFRm 驱动的具有 PIK3CA/PTEN 改变的非小细胞肺癌中通过 AKT 抑制克服奥希替尼耐药

目的：奥希替尼是一种表皮生长因子受体酪氨酸激酶抑制剂（EGFR-TKI），适用于治疗 EGFR 突变（EGFRm）驱动的肺腺癌。奥希替尼显着改善一线治疗的 EGFRm 晚期 NSCLC 患者的无进展生存期。尽管疾病得到了持久的控制，但大多数接受奥希替尼治疗的患者最终都会出现疾病进展。实验设计：对第一线试验（第 3 期，FLAURA 试验）和二线试验（第 3 期，AURA3 试验）中接受奥希替尼治疗的患者的进展血浆样本进行 ctDNA 分析，结果显示 PIK3CA/AKT/PTEN 改变的发生率很高。使用 CRISPR 工程化 NSCLC 细胞系和 PXD 模型的体外和体内证据支持 PIK3CA 和 PTEN 突变在奥希替尼耐药性发展中的功能作用。结果：这些改变在功能上是相关的，因为具有工程化 PIK3CA/AKT/PTEN 改变的 EGFRm NSCLC 细胞对奥希替尼产生耐药性，并且可以通过奥希替尼和 AKT 抑制剂 capivasertib 的联合治疗重新敏化。此外，与未改变的模型相比，具有 PIK3CA/AKT/PTEN 改变的异种移植物和 PDX 体内模型对奥希替尼的敏感性有限，并且在这些双突变模型中，与单独使用奥希替尼相比，capivasertib 和奥希替尼组合产生了改善的抗肿瘤效果。结论：总的来说，这种方法为 EGFRm 驱动的 NSCLC 患者提供了一种潜在的治疗策略，这些患者通过 PIK3CA/AKT/PTEN 改变对奥西替尼反应不佳或产生耐药性。