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

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.