代谢重编程在基底样乳腺癌对JAK2抑制剂药物抵抗过程中的作用和机制研究

JAK/STAT信号通路对于基底样乳腺癌细胞的生存和增殖很重要，靶向抑制JAK/STAT是当前针对基底样乳腺癌临床试验的重要方向。但是基底样乳腺癌细胞对JAK2抑制剂存在药物抵抗现象，其分子机制尚不清楚。本研究发现JAK2抑制剂TG101209促进基底样乳腺癌细胞中ZSWIM4基因的表达升高，沉默该基因可以促进TG101209的杀伤力和1,25二羟基维生素D3的表达；另一方面，TG101209的长时间处理增强了脂肪酸β氧化作用，并促进脂肪酸β氧化途径中的催化酶MLYCD和ACOT8基因的表达升高，沉默这两个基因可以有效的克服癌细胞对JAK2抑制剂的药物抵抗。该项目将揭示对JAK2抑制剂耐药的基底样乳腺癌细胞的基因表达谱和代谢物表达谱，从代谢重编程的角度解析癌细胞对JAK2抑制剂药物抵抗的分子机制，为基底样乳腺癌临床治疗提出有效的靶向治疗组合方案。

JAK/STAT signaling is critical for the survival and proliferation of basal-like breast cancer (BLBC) cells. Currently, targeted inhibition of JAK/STAT is an important direction for clinical trials of BLBC. However, the underlying mechanisms of JAK2 inhibition resistance of BLBC remain unknown. In this study, we found that JAK2 inhibitor TG101209 can induce ZSWIM4 gene expression in BLBC cells, ZSWIM4-silencing enhanced the killing effect of TG101209 and the production of 1,25(OH)2VitD3. On the other hand, the long-term treatment of TG101209 stimulated the β-oxidation of fatty acid, and promoted the expression of MLYCD and ACOT8 genes, which knockdown of these two genes can effectively overcome the JAK2 inhibition resistance. This project will reveal the gene and metabolite expression profile of JAK2 inhibition resistant BLBC cells, clarify the molecular mechanism of JAK2 inhibition resistance of cancer cells from the perspective of metabolic reprogramming, and propose effective combinations of targeted therapy for BLBC.