BET抑制剂已被证明可以减少肿瘤生长，在临床试验和临床前模型中均有所表现。然而，毒性和抗药性的快速出现限制了它们的临床应用。为了确定JQ1 BET抑制剂抗药性形成的状态变化，我们重新分析了JQ1敏感和抗药性SUM149和SUM159三阴性乳腺癌细胞系的单细胞RNA测序数据。亲本和JQ1抗药性SUM149和SUM159表现出干细胞样和胚胎滞育（SCLED）细胞状态，以及SCLED细胞状态和转化细胞状态之间的中间细胞状态，该中间细胞状态存在于未经治疗和接受JQ1治疗的细胞中，并且有多种JQ1耐药细胞状态。中间细胞状态的转录特征签名而不是SCLED状态的转录特征签名能够预测基底样乳腺癌患者的不良预后，表明从SCLED状态转变为耐药状态对患者预后有所贡献。SUM149和SUM159进入中间细胞状态时，CD9 tetraspanin的表达增加。在体外实验中，CD9敲低或抑制使细胞对多种靶向和细胞毒性药物敏感。重要的是，CD9敲低或阻断使SUM149对JQ1在体内敏感，通过将细胞困在SCLED状态并限制向耐药状态转变。因此，CD9在从SCLED状态转变为耐药细胞状态的转化过程中显得至关重要，并且有望作为基底样乳腺癌的治疗靶点进行探究。© 2023年。细胞死亡和分化学会（ADMC）。

Bromo- and extra-terminal domain (BET) inhibitors (BETi) have been shown to decrease tumor growth in preclinical models and clinical trials. However, toxicity and rapid emergence of resistance have limited their clinical implementation. To identify state changes underlying acquisition of resistance to the JQ1 BETi, we reanalyzed single-cell RNAseq data from JQ1 sensitive and resistant SUM149 and SUM159 triple-negative breast cancer cell lines. Parental and JQ1-resistant SUM149 and SUM159 exhibited a stem cell-like and embryonic diapause (SCLED) cell state as well as a transitional cell state between the SCLED state that is present in both treatment naïve and JQ1 treated cells, and a number of JQ1 resistant cell states. A transitional cell state transcriptional signature but not a SCLED state transcriptional signature predicted worsened outcomes in basal-like breast cancer patients suggesting that transit from the SCLED state to drug-resistant states contributes to patient outcomes. Entry of SUM149 and SUM159 into the transitional cell state was characterized by elevated expression of the CD9 tetraspanin. Knockdown or inhibition of CD9-sensitized cells to multiple targeted and cytotoxic drugs in vitro. Importantly, CD9 knockdown or blockade sensitized SUM149 to JQ1 in vivo by trapping cells in the SCLED state and limiting transit to resistant cell states. Thus, CD9 appears to be critical for the transition from a SCLED state into treatment-resistant cell states and warrants exploration as a therapeutic target in basal-like breast cancer.© 2023. Cell Death Differentiation Association (ADMC).