伊马替尼耐药是胃肠间质瘤（GIST）治疗中亟待解决的难题。申请人前期筛选了在伊马替尼耐药GIST中的几条重要通路，并致力于寻找有效的治疗靶点。最近通过20对肿瘤及癌旁组织转录组测序发现CAMK1D在GIST肿瘤组织中高表达，且在耐药肿瘤中表达更高。进而应用高内涵筛选技术筛查差异表达基因，发现敲减CAMK1D后有更显著的增殖抑制效用。生信分析表明CAMK1D高表达与差的预后相关。CAMK1D敲除可抑制多种GIST耐药细胞的增殖、克隆形成及迁移，促进耐药细胞凋亡，与伊马替尼联用具有协同作用，一定程度上逆转耐药。进一步预实验推测：靶向CAMK1D通过对MAPK/ERK通路的磷酸化调控发挥相应效应。本课题旨在获得靶向CAMK1D逆转耐药的充分证据；观察伊马替尼联合CAMK1D抑制剂在逆转耐药中的疗效；通过免疫共沉淀、基因芯片等手段阐明具体调控机制，为确立CAMK1D作为GIST新靶点提供科学依据。

Imatinib resistance remains an urgent clinical challenge in the treatment of gastrointestinal stromal tumor (GIST). We screened several important pathways in imatinib-resistant GIST，and made efforts to identify effective therapeutic targets. Recently, transcriptome sequencing of 20 pairs of tumors and adjacent normal tissues revealed that CAMK1D was highly expressed in GIST tumor tissues. And the expression of CAMK1D was higher in imatinib-resistant tumor tissues. The high-intension screening technique was used to further detect differentially expressed genes, and found that knocking down CAMK1D had a more significant inhibitory effect on cell proliferation. Bioinformatics analysis confirmed that high expression of CAMK1D was associated with poor prognosis. In several imatinib-resistant GIST cell lines, CAMK1D knockout inhibited the cell proliferation, clone formation and migration, promoted the apoptosis of drug-resistant cells, showed synergistic effect combined with imatinib and reversed imatinib resistance to some extent. Further pre-experiment speculated that CAMK1D exerted the effects through phosphorylation-dependent regulation of MAPK/ERK pathway. Our study will：（1）obtain sufficient evidence of reversing imatinib resistance by targeting CAMK1D; （2）observe the efficacy of imatinib combined with CAMK1D inhibitors in reversing imatinib resistance; （3）explore the specific regulatory mechanism through immunoprecipitation, microarray and other means, and provide scientific basis for the establishment of CAMK1D as a new therapeutic target for GIST.