Rare case of apatinib acquired resistance induced by point mutation of WRN p.V697F through activation of the PI3K/AKT apoptosis-inhibiting pathway

Abstract

Targeted therapy has become the main treatment for non-small cell lung cancer (NSCLC). Apatinib is a new antiangiogenic antitumor drug developed in China which targets vascular endothelial growth factor receptor-2 (VEGFR-2). We recently treated a 50-year-old female patient who underwent a bronchoscopic biopsy and was subsequently pathologically diagnosed with squamous cell carcinoma of NSCLC. EML4-ALK and MINPP1 & PAPSS2-PTEN fusions were found to be present in tumor tissue and blood. Sequential targeted therapy was commenced with gemcitabine + cisplatin, docetaxel, tegafur, gimeracil, oteracil potassium capsules + carboplatin, and other third-line chemotherapy involving antineoplastic therapy, but unfortunately the patient showed primary drug resistance to this treatment regimen. Crizotinib was administered but was found to be ineffective. After two months of treatment, the disease had progressed and next generation sequencing (NGS) was subsequently performed. Apatinib was administered thereafter and the patient's symptoms improved after one week. Following administration for one month, CT scan revealed that the primary lung tumor lesions were significantly necrotic and they were narrowed. The patient's symptoms of coughing, phlegm production, and wheezing had also reduced. Her lung disease was under stable control 2.5 months later, but abdominal CT unfortunately revealed a suspected new nidus in the liver. A third gene mutation detection test showed that ALK and PTEN genetic mutations were obviously decreased; however, the patient was found to have developed WRN p.V697F (c.G2089T) point mutation, which was a new gene mutation. We suspected that the WRN gene mutation had led to apatinib resistance. We determined the absolute position of this point mutation to be chr8:30969131 with a transcript number of NM_000553.4. We retrieved information on human somatic cells from the ExAC, 1000 Genomes Browser, ESP database and PubMed databases. All the results indicated that the mutation identified in this study has not been previously reported worldwide.

Keywords: Liquid biopsy; WRN; apatinib; lung cancer; targeted therapy.