Could microtubule inhibitors be the best choice of therapy in gastric cancer with high immune activity: mutant DYNC1H1 as a biomarker.
Could microtubule inhibitors be the best choice of therapy in gastric cancer with high immune activity: mutant DYNC1H1 as a biomarker.
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DOI：
10.18632/aging.104084
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发表时间：
2020-11-20
期刊：
影响因子：
--
通讯作者：
Li Z
中科院分区：
文献类型：
--
作者：
Bai J;Yang B;Shi R;Shao X;Yang Y;Wang F;Xiao J;Qu X;Liu Y;Zhang Y;Li Z
免疫检查点阻断（ICB）在各种癌症中取得了前所未有的突破，包括具有高免疫活性的胃癌（GC）（MSI-H或TMB-H），但ICB的临床获益中等。在这里，我们的目标是确定可以改善GC结果的最合适药物。我们首先在TCGA-STAD队列中将MSI-H和TMB-H GC样本分别与正常样本进行比较。之后，连接图数据库重新利用了9种候选药物（CMap评分< -90）。然后，通过GSEA筛选微管抑制剂（MTIs）作为显著的候选药物，其代表性基因集强烈富集（p < 0.05）。GDSC数据库验证了具有MSI-H和TMB-H的GC细胞中的一些MTIs的更高活性（p < 0.05）。此外，基于NCI-60癌细胞系组，一些MTIs活性与突变型动力蛋白胞质1重链1（DYNC 1H 1）正相关（p < 0.05）。DYNC 1H 1在胃癌中的表达频率较高，与TMB-H和MSI-H呈正相关。DYNC 1H 1突变可能伴随MTIs相关基因的下调或改变MTIs的结合口袋而致敏。总体而言，本研究表明，一些MTIs可能是治疗具有高免疫活性的GC的最佳候选药物，特别是DYNC 1H 1突变的患者。
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.
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影响因子：
8.8
作者：
Baba, H.;Watanabe, M.;Okabe, H.;Miyamoto, Y.;Sakamoto, Y.;Baba, Y.;Iwatsuki, M.;Chikamoto, A.;Beppu, T.
通讯作者：
Beppu, T.
影响因子：
14.9
作者：
Colaprico A;Silva TC;Olsen C;Garofano L;Cava C;Garolini D;Sabedot TS;Malta TM;Pagnotta SM;Castiglioni I;Ceccarelli M;Bontempi G;Noushmehr H
通讯作者：
Noushmehr H
影响因子：
4.6
作者：
Bonneville R;Krook MA;Kautto EA;Miya J;Wing MR;Chen HZ;Reeser JW;Yu L;Roychowdhury S
通讯作者：
Roychowdhury S
影响因子：
168.9
作者：
GILGRANDE, LA;RODRIGUEZCAABEIRO, F;DALRE, R
通讯作者：
DALRE, R
DOI：
10.1158/1078-0432.ccr-09-3233
发表时间：
2010-06-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Huang GS;Brouwer-Visser J;Ramirez MJ;Kim CH;Hebert TM;Lin J;Arias-Pulido H;Qualls CR;Prossnitz ER;Goldberg GL;Smith HO;Horwitz SB
通讯作者：
Horwitz SB