Ming Ruijie, Zhang Han, Wu Huan, Zhan Fangbiao, Huang Xiaoping, Liu Huawen
Department of Oncology, Chongqing University Three Gorges Hospital, Chongqing, China.
School of Medicine, Chongqing University, Chongqing, China.
Front Pharmacol. 2025 Apr 15;16:1590363. doi: 10.3389/fphar.2025.1590363. eCollection 2025.
Endocrine therapy combined with CDK4/6 inhibitors remains a standard treatment for ER+ breast cancer, yet resistance is a prevalent challenge. This study explores the role of N6-methyladenosine (m6A) modifications, influenced by m6A-SNPs, in shaping therapy resistance, utilizing single-cell RNA sequencing to delineate the underlying molecular mechanisms.
We integrated genome-wide association study data with single-cell transcriptomic profiles from ER+ breast cancer patients, focusing on differences between resistant and sensitive responses to CDK4/6 inhibitors. m6A-SNPs were identified and analyzed for their impact on gene expression and interactions with RNA-binding proteins, with a particular focus on their roles within key cellular pathways.
The study identified crucial m6A-SNPs associated with therapy resistance. Notably, changes in the expression of FILIP1L and TOM1L1, related to these SNPs, were mapped using pseudotime trajectory analysis, which traced the evolution from sensitive to resistant cellular states. FILIP1L and TOM1L1 exhibited dynamic expression changes along the trajectory, correlating with significant shifts in cell fate decisions. These findings underscore their potential roles as mediators in the development of resistance, particularly through their involvement in the PI3K-Akt and Wnt signaling pathways, critical in cancer progression and drug resistance.
Our findings emphasize the importance of m6A-SNPs in influencing resistance to therapy in ER+ breast cancer. The dynamic regulation of FILIP1L and TOM1L1 along the developmental trajectory of tumor cells from sensitivity to resistance provides insights into the molecular complexity of therapy resistance. These results pave the way for developing targeted therapies that modify m6A-driven pathways, offering new strategies to counteract resistance and improve patient outcomes.
内分泌治疗联合CDK4/6抑制剂仍然是雌激素受体阳性（ER+）乳腺癌的标准治疗方法，但耐药性是一个普遍存在的挑战。本研究利用单细胞RNA测序来描绘潜在的分子机制，探讨受m6A单核苷酸多态性（m6A-SNPs）影响的N6-甲基腺苷（m6A）修饰在形成治疗耐药性中的作用。
我们将全基因组关联研究数据与ER+乳腺癌患者的单细胞转录组图谱相结合，重点关注对CDK4/6抑制剂耐药和敏感反应之间的差异。鉴定并分析了m6A-SNPs对基因表达的影响及其与RNA结合蛋白的相互作用，特别关注它们在关键细胞通路中的作用。
该研究确定了与治疗耐药性相关的关键m6A-SNPs。值得注意的是，利用伪时间轨迹分析绘制了与这些SNP相关的FILIP1L和TOM1L1表达变化，该分析追踪了从敏感细胞状态到耐药细胞状态的演变。FILIP1L和TOM1L1在轨迹上表现出动态表达变化，与细胞命运决定的显著转变相关。这些发现强调了它们作为耐药性发展中介的潜在作用，特别是通过它们参与PI3K-Akt和Wnt信号通路，这两条通路在癌症进展和耐药性中至关重要。
我们的研究结果强调了m6A-SNPs在影响ER+乳腺癌治疗耐药性方面的重要性。FILIP1L和TOM1L1在肿瘤细胞从敏感到耐药的发育轨迹上的动态调节为治疗耐药性的分子复杂性提供了见解。这些结果为开发修饰m6A驱动通路的靶向治疗铺平了道路，为对抗耐药性和改善患者预后提供了新策略。
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