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Front. Pharmacol. | doi: 10.3389/fphar.2019.00944

Discovery of Novel Biomarkers of Therapeutic Responses in Han Chinese Pemetrexed-based Treated Advanced NSCLC Patients

 Sheng y. Qin1, 2, 3*, Zhan h. Wang4*,  Jin h. Zhu1, 3*, Xiao q. Zhang5, Di Zhang1, 3, 6, Li h. Huang7, Guo r. Li8, Luan Chen9,  Jing s. Ma3, Mo Li3, Mu y. Wei3,  Wei Zhou3 and Chen x. Zhou3
  • 1School of Life Sciences, Anhui Medical University, China
  • 2Third Affiliated Hospital of Guangzhou Medical University, China
  • 3Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Shanghai Jiao Tong University, China
  • 4Department of General Surgery, Luoyang Central Hospital, China
  • 5School of Medicine, Shanghai Jiao Tong University, China
  • 6School of Life Sciences, Anhui Medical University, China
  • 7Department of Oncology, Shanghai Pulmonary Hospital, China
  • 8College of Life Sciences, Shandong Normal University, China
  • 9Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Shanghai Jiao Tong University, China

Pemetrexed, one of the most commonly used drugs in advanced non-small cell lung cancer (NSCLC) therapies, often leads to various therapeutic responses in patients. These therapeutic responses to pemetrexed, including adverse drug reactions (ADRs) and its intended therapeutic effects, have been demonstrated to be highly individual-specific. Such difference in therapeutic responses across individual may be caused by the unique genetic variations in each patient. However, only a few pemetrexed-based studies have been performed using Han Chinese patients. In this study, we aimed to identify genetic signatures of therapeutic responses of pemetrexed-based treatment using 203 Han Chinese advanced NSCLC patients. All the participants received 2 different types of therapies: (1) treatment with only pemetrexed; (2) treatment with both pemetrexed plus platinum (mainly cisplatin and carboplatin). We then performed a genetic association analysis on 16 selected SNPs in 7 genes using these 2 groups. The analysis of patients receiving only pemetrexed suggested that the SNP rs1051298 on SLC19A1 gene (c.*746C>T) increased the risk of all ADRs (collected all types of ADRs) in different cycles of pemetrexed therapy (1-2 cycle: P = 0.0059, OR = 3.143; 1-4 cycle: P = 0.0072, OR = 2.340; 1-6 cycle: P = 0.0071, OR = 2.243). This influence of rs1051298 is particularly significant in terms of liver injury (1-4 cycle: P = 0.0056, OR = 3.863; 1-6 cycle: P = 0.0071, OR = 3.466). In all the patients, including patients who received both pemetrexed plus platinum, SNP rs1801133 on MTHFR gene (665C>T) was found to be significantly associated with hematological ADRs in 1-2 cycle (P = 0.0079, OR = 3.566). Additionally, we discovered that SNP rs12995526 (c.815-102T>C) in the ATIC gene and SNP rs11545077 (c.91G>T) in the GGH gene were associated with both ADRs and therapeutic effects. In sum, our study identified several potential biomarkers that were significantly associated with ADRs and therapeutic effects of pemetrexed-related treatments using Han Chinese patients. Our discoveries will provide important clues for personalized pemetrexed-based treatment design that is for Han Chinese NSCLC patients in the future.

Keywords: pemetrexed, adverse drug reactions, therapeutic effects, Non-small cell lung cancer, biomarker, single nucleotide polymorphism (SNP)

Received: 29 Nov 2018; Accepted: 24 Jul 2019.

Copyright: © 2019 Qin, Wang, Zhu, Zhang, Zhang, Huang, Li, Chen, Ma, Li, Wei, Zhou and Zhou. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence:
Prof. Sheng y. Qin, School of Life Sciences, Anhui Medical University, Hefei, Anhui Province, China, chinsir@sjtu.edu.cn
Dr. Zhan h. Wang, Department of General Surgery, Luoyang Central Hospital, Luoyang, China, zhanhuiwangxyjt@163.com
PhD. Jin h. Zhu, School of Life Sciences, Anhui Medical University, Hefei, Anhui Province, China, zhujinhang@sjtu.edu.cn