Nikanjam Mina, Kato Shumei, Adashek Jacob J, Kurzrock Razelle
Center for Personalized Cancer Therapy and Division of Hematology and Oncology, UC San Diego Moores Cancer Center, San Diego, USA.
Department of Internal Medicine, University of South Florida, Tampa, FL, USA.
Clin Oncol Case Rep. 2022 Jan;5(1). Epub 2021 Dec 15.
Epidermal Growth Factor Receptor (EGFR) exon 20 insertion alterations represent 4%-10% of all EGFR mutations in Non-Small Cell Lung Cancer (NSCLC) and result in resistance to standard EGFR-directed therapies. EGFR exon 20 insertions restrict the size of the kinase pocket, prohibiting the entry of approved EGFR kinase inhibitor drugs. Structural In Silico modeling also predicts that EGFR exon 20 insertion anomalies increase attractive electrostatic dimerization, hence stabilizing the activating dimer configuration. EGFR antibodies such as cetuximab that interfere with dimerization may lead to responses. We identified three non-smoking patients with NSCLC and EGFR exon 20 insertions treated with cetuximab-based therapy. All three patients demonstrated clinical benefit. A 58-year-old woman achieved prolonged stable disease lasting 9 months, while a 76-year-old woman and 38-year-old man maintained a partial response with progression-free survivals of 13 months and 32 months, respectively. In conclusion, cetuximab merits further investigation as it appears to be an additional promising therapy for overcoming EGFR exon 20 insertion-related resistance.
表皮生长因子受体（EGFR）外显子20插入改变占非小细胞肺癌（NSCLC）所有EGFR突变的4%-10%，并导致对标准EGFR靶向治疗产生耐药性。EGFR外显子20插入会限制激酶口袋的大小，阻止已获批的EGFR激酶抑制剂药物进入。计算机模拟结构建模还预测，EGFR外显子20插入异常会增加有吸引力的静电二聚化，从而稳定激活二聚体构型。干扰二聚化的EGFR抗体如西妥昔单抗可能会产生疗效。我们确定了3例非吸烟的NSCLC患者，其EGFR外显子20插入，接受了以西妥昔单抗为基础的治疗。所有3例患者均显示出临床获益。一名58岁女性实现了长达9个月的疾病长期稳定，而一名76岁女性和一名38岁男性维持了部分缓解，无进展生存期分别为13个月和32个月。总之，西妥昔单抗值得进一步研究，因为它似乎是克服EGFR外显子20插入相关耐药性的另一种有前景的治疗方法。
