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Competitive evolution of NSCLC tumor clones and the drug resistance mechanism of first-generation EGFR-TKIs in Chinese NSCLC patients
Authors:PICB    Time:2018-12-24   Read:195

The research Group headed by Li Yixue, group leader, a Professor of Institute of Computational Biology, Institute of Nutrition and Health, made progress in the study of “Competitive evolution of NSCLC tumor clones and the drug resistance mechanism of first-generation EGFR-TKIs in Chinese NSCLC patients”.  The study Published in Heliyon, a newly launched Elsevier’s science magazine.

The first-generation EGFR-TKIs significantly improved the survival and quality of life of patients with advanced non-small cell lung cancer (NSCLC), but patients developed resistance after an average of 9 to 13 months. Although there are many work based on tissue biopsy to study the gene mutation profile after drug resistance, there are still several problems to be solved: 1. How to analyze the tumor resistance related gene mutation profile under the premise of comprehensive coverage of tumor heterogeneity; 2. How to establish effective tumor treatment methods by dynamically monitoring changes in tumor sub-clones. To this end, the study used blood biopsy instead of tissue biopsy to achieve full coverage of tumor heterogeneity and dynamic monitoring of tumor sub-clonal evolution. The study collected 53 patients with advanced non-small cell lung cancer who had drug-sensitive gene mutations of the first-generation EGFR-TKIs. By dynamically collecting blood samples from patients, the circulating tumor DNA (ctDNA) in the blood was enriched for deep sequencing. SNV and INDEL were accurately analyzed and identified using virtual molecular labeling technology. The results of the study showed that: 1. The lung cancer-associated tumor gene mutation profile obtained by liquid biopsy was highly coincident with the previous comprehensive results from tissue samples. 2. The drug resistance mutation profile of the Chinese population was obtained: EGFR p.T790M (45.28%), EGRFR point mutation (33.9%), KRAS & NRAS point mutation (15.09%). Among them, T790M mutation has spatial and temporal heterogeneity, and 32.65% of patients with drug resistance mutations involved multiple genes and found two new repetitive drug resistance mutation sites. 3. The proportion of non-drug sensitive EGFR-/- sub-clones in competitive evolution determines the effect of subsequent treatment options and prognosis.

This study shows that tracking the competitive evolution of tumor clones by ctDNA dynamic detection, combined with radiotherapy and chemotherapy and targeted drugs to properly intervention in the processes of competitive evolution of tumor sub-clones, may provide a new tumor treatment. 

This work collaborated with Zhou Songwen’s research group of the Department of Oncology, Shanghai Pulmonary Hospital. Associate Professor Deng Xingfang from Shanghai Pulmonary Hospital and Dr. Wu Leilei from Li Yixue’s research group and Dr. Li Chao from Smartquerier LTD. are co-first authors. Professor Ding Chunming from Wenzhou Medical University has also made important contributions to the experimental verification of this study.