Translational Medicine, Oncology R&D, AstraZeneca, Cambridge, UK.
Bioscience, Oncology R&D, AstraZeneca, Cambridge, UK.
Nat Commun. 2021 Mar 19;12(1):1780. doi: 10.1038/s41467-021-22057-8.
Advanced non-small-cell lung cancer (NSCLC) patients with EGFR T790M-positive tumours benefit from osimertinib, an epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI). Here we show that the size of the EGFR T790M-positive clone impacts response to osimertinib. T790M subclonality, as assessed by a retrospective NGS analysis of 289 baseline plasma ctDNA samples from T790M-positive advanced NSCLC patients from the AURA3 phase III trial, is associated with shorter progression-free survival (PFS), both in the osimertinib and the chemotherapy-treated patients. Both baseline and longitudinal ctDNA profiling indicate that the T790M subclonal tumours are enriched for PIK3CA alterations, which we demonstrate to confer resistance to osimertinib in vitro that can be partially reversed by PI3K pathway inhibitors. Overall, our results elucidate the impact of tumour heterogeneity on response to osimertinib in advanced stage NSCLC patients and could help define appropriate combination therapies in these patients.
表皮生长因子受体-酪氨酸激酶抑制剂（EGFR-TKI）奥希替尼可使 EGFR T790M 阳性肿瘤的晚期非小细胞肺癌（NSCLC）患者获益。在此，我们发现 EGFR T790M 阳性克隆的大小影响奥希替尼的应答。通过对 AURA3 期临床试验中 289 例 T790M 阳性晚期 NSCLC 患者的 289 例基线血浆 ctDNA 样本进行回顾性 NGS 分析，T790M 亚克隆性与无进展生存期（PFS）相关，奥希替尼和化疗治疗的患者均如此。基线和纵向 ctDNA 分析均表明，T790M 亚克隆肿瘤富含 PIK3CA 改变，我们证明这些改变在体外赋予奥希替尼耐药性，PI3K 通路抑制剂可部分逆转这种耐药性。总的来说，我们的研究结果阐明了肿瘤异质性对晚期 NSCLC 患者接受奥希替尼治疗的影响，并可能有助于确定这些患者的合适联合治疗方案。
