Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.
Samsung Genome Institute, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea; Department of Health Science and Technology, Samsung Advanced Institute of Health Science and Technology, Sungkyunkwan University, Seoul, Republic of Korea.
Lung Cancer. 2019 Aug;134:7-15. doi: 10.1016/j.lungcan.2019.05.024. Epub 2019 May 24.
Adenocarcinoma (ADC) to squamous cell carcinoma (SCC) transformation (AST) is reported in epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer after tyrosine kinase inhibitor (TKI) failure. However, little is known about the underlying genomic changes during the AST process.
We retrospectively reviewed our tissue database collected after first- or second- generation EGFR TKI resistance (n = 263) and identified 3 cases of AST. The additional case was acquired from the osimertinib resistance sample. Deep target sequencing (381 genes) using paired samples from 4 patients with AST after EGFR TKI treatment was performed. The histology of each sample was confirmed by TTF-1 and p63 immunohistochemistry. The patients received first- or second-generation EGFR TKI as an initial treatment.
Overall incidence of AST was 1.1% (3/263). Transformed SCC acquired genomic alterations related to the PI3K/AKT/mTOR pathway, in addition to the initial EGFR mutation. In a representative case, two separate sub-clones, with a PTEN nonsense mutation and EGFR p.T790 M mutation, were observed without histologic transformation at the time of gefitinib resistance. After subsequent treatment with osimertinib, SCC transformation was observed with the disappearance of the EGFR p.T790 M mutation and acquired copy number loss in PTEN. Adopting the sub-clonal fraction model elucidates the sub-clonal evolution process of the PTEN mutant sub-clone toward AST under the background of EGFR mutation. The rest of the transformed samples also had acquired genomic alterations in PTEN, LKB1, PIK3CA, or RICTOR, which are related to the PI3K/AKT/mTOR pathway.
Paired genomic analysis from our sample provides early clinical evidence of the ADC to SCC lineage transition that might be provoked by an alteration in the PI3K/AKT/mTOR pathway during EGFR TKI treatment. This finding could potentially broaden the known spectrum of EGFR TKI resistance mechanisms.
表皮生长因子受体（EGFR）突变型非小细胞肺癌患者在酪氨酸激酶抑制剂（TKI）治疗失败后，有报道称发生腺癌（ADC）向鳞状细胞癌（SCC）转化（AST）。然而，对于 AST 过程中潜在的基因组变化知之甚少。
我们回顾性地查阅了我们在第一代或第二代 EGFR TKI 耐药后收集的组织数据库（n=263），并确定了 3 例 AST。另外一个病例是从奥希替尼耐药样本中获得的。对 4 例接受 EGFR TKI 治疗后发生 AST 的患者的配对样本进行了深度靶向测序（381 个基因）。每个样本的组织学均通过 TTF-1 和 p63 免疫组化进行确认。这些患者接受第一代或第二代 EGFR TKI 作为初始治疗。
AST 的总体发生率为 1.1%（3/263）。转化型 SCC 获得了与 PI3K/AKT/mTOR 通路相关的基因组改变，除了最初的 EGFR 突变。在一个代表性病例中，在吉非替尼耐药时，观察到两个独立的亚克隆，一个具有 PTEN 无义突变，另一个具有 EGFR p.T790M 突变，而没有组织学转化。随后接受奥希替尼治疗后，观察到 SCC 转化，同时 EGFR p.T790M 突变消失，并出现 PTEN 拷贝数缺失。采用亚克隆分数模型阐明了在 EGFR 突变背景下，PTEN 突变亚克隆向 AST 发展的亚克隆进化过程。其余转化样本也在 PTEN、LKB1、PIK3CA 或 RICTOR 中获得了基因组改变，这些改变与 PI3K/AKT/mTOR 通路相关。
我们的样本进行配对基因组分析，为 EGFR TKI 治疗过程中 PI3K/AKT/mTOR 通路改变可能引发 ADC 向 SCC 谱系转化提供了早期临床证据。这一发现可能会拓宽已知的 EGFR TKI 耐药机制的范围。
