Klempner Samuel J, Mehta Pareen, Schrock Alexa B, Ali Siraj M, Ou Sai-Hong Ignatius
The Angeles Clinic and Research Institute, Los Angeles, CA, USA.
Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
Lung Cancer (Auckl). 2017 Dec 6;8:241-247. doi: 10.2147/LCTT.S147129. eCollection 2017.
Acquired resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) is a universal event and limits clinical efficacy. The third-generation EGFR inhibitor osimertinib is active in EGFR-mutant/T790M positive non-small-cell lung cancer. Mechanisms of acquired resistance are emerging, and here we describe a -oriented solvent-front EGFR G796S mutation as the resistance mechanism observed in a progression biopsy and circulating tumor DNA (ctDNA) from a patient with initial response followed by progression on osimertinib. This is one of the earliest reports of a sole solvent-front tertiary EGFR mutation as a resistance mechanism to osimertinib. Our case suggests a monoclonal resistance mechanism. We review the importance of the solvent-front residues across TKIs and describe known osimertinib resistance mechanisms. We observe that nearly all clinical osimertinib-resistant tertiary EGFR mutations are oriented in with EGFR T790M. This case highlights the importance of mutations affecting EGFR kinase domains and supports the feasibility of broad panel ctDNA assays for detection of novel acquired resistance and tumor heterogeneity in routine clinical care.
对表皮生长因子受体（EGFR）酪氨酸激酶抑制剂（TKI）产生获得性耐药是一种普遍现象，会限制临床疗效。第三代EGFR抑制剂奥希替尼对EGFR突变/T790M阳性非小细胞肺癌有效。获得性耐药机制正在逐渐明晰，在此我们描述了一种以溶剂前沿为导向的EGFR G796S突变，该突变是在一名最初对奥希替尼有反应但随后病情进展的患者的进展期活检组织和循环肿瘤DNA（ctDNA）中观察到的耐药机制。这是最早报道的单一溶剂前沿三级EGFR突变作为对奥希替尼耐药机制的案例之一。我们的病例提示了一种单克隆耐药机制。我们回顾了溶剂前沿残基在各种TKI中的重要性，并描述了已知的奥希替尼耐药机制。我们观察到，几乎所有临床奥希替尼耐药的三级EGFR突变都与EGFR T790M呈同向排列。该病例突出了影响EGFR激酶结构域的突变的重要性，并支持在常规临床护理中进行广泛的ctDNA检测以检测新出现的获得性耐药和肿瘤异质性的可行性。
