Research Paper Advance Articles

Could microtubule inhibitors be the best choice of therapy in gastric cancer with high immune activity: mutant DYNC1H1 as a biomarker

Jin Bai1,2,3,4, , BoWen Yang1,2,3,4, , Ruichuan Shi1,2,3,4, , Xinye Shao1,2,3,4, , Yujing Yang1,2,3,4, , Fang Wang1,2,3,4, , Jiawen Xiao5, , Xiujuan Qu1,2,3,4, , Yunpeng Liu1,2,3,4, , Ye Zhang6, , Zhi Li1,2,3,4, ,

  • 1 Department of Medical Oncology, The First Hospital of China Medical University, Shenyang 110001, China
  • 2 Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, The First Hospital of China Medical University, Shenyang 110001, China
  • 3 Liaoning Province Clinical Research Center for Cancer, Shenyang 110001, China
  • 4 Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, Shenyang 110001, China
  • 5 Department of Medical Oncology, Shenyang Fifth People Hospital, Tiexi District, Shenyang 110001, China
  • 6 Laboratory I of Cancer Institute, The First Hospital of China Medical University, Shenyang 110001, China

Received: January 13, 2020       Accepted: August 27, 2020       Published: November 20, 2020      

https://doi.org/10.18632/aging.104084
How to Cite

Copyright © 2020 Bai et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Abstract

Immune checkpoint blockade (ICB) has achieved unprecedented breakthroughs in various cancers, including gastric cancer (GC) with high immune activity (MSI-H or TMB-H), yet clinical benefits from ICB were moderate. Here we aimed to identify the most appropriate drugs which can improve outcomes in GC. We firstly compared MSI-H and TMB-H GC samples with normal samples in TCGA-STAD cohort, respectively. After that, Connectivity Map database repurposed nine candidate drugs (CMap score < -90). Then, microtubule inhibitors (MTIs) were screened as the significant candidate drugs with their representative gene sets strongly enriched (p < 0.05) via GSEA. GDSC database validated higher activities of some MTIs in GC cells with MSI-H and TMB-H (p < 0.05). Furthermore, some MTIs activities were positively associated with mutant Dynein Cytoplasmic 1 Heavy Chain 1 (DYNC1H1) (p < 0.05) based on NCI-60 cancer cell line panel. DYNC1H1 was high frequently alteration in GC and was positively associated with TMB-H and MSI-H. Mutant DYNC1H1 may be accompanied with down-regulation of MTIs-related genes in GC or change the binding pocket to sensitize MTIs. Overall, this study suggested that some MTIs may be the best candidate drugs to treat GC with high immune activity, especially patients with DYNC1H1 mutated.

Abbreviations

ICB: immune checkpoint blockade; GC: gastric cancer; STAD: stomach adenocarcinoma; TCGA: The Cancer Genome Atlas; MSI-H: high microsatellite instability; TMB-H: high tumor mutational burden; CMap: Connectivity Map; MTIs: microtubule inhibitors; DYNC1H1: Dynein Cytoplasmic 1 Heavy Chain 1; DEGs: differentially expressed genes; GSEA: gene sets enrichment analysis; PPI: protein-protein interaction; NCI-60: National Cancer Institute 60; GDSC: genomics of drug sensitivity in cancer; IC50: inhibitory concentration; GI50: growth inhibition; UCEC: Uterine Corpus Endo-metrial Carcinoma.