治疗耐药性是对抗炎性乳腺癌（IBC）的一个重大障碍，增加了其治疗的复杂性。为了研究这些机制，我们仅在临床前模型中使用转录组和蛋白质组分析以及 IBC 患者治疗反应的相关性进行了全面分析。其中包括源自初治患者的 SUM149 细胞系，以及获得性耐药 (rSUM149) 和其他处于耐药逆转状态的 (rrSUM149) 细胞系，旨在揭示耐药网络。我们鉴定了与获得耐药性相关的特定核糖体蛋白。这些与 pERK、CDK1、XIAP 和 SOD2 等分子标记水平升高相关。虽然 rrSUM149 细胞中的耐药逆转在很大程度上使表达谱正常化，但 VIPER 分析显示核糖体过程相关蛋白（AGO2、Exportin 1、RPL5）持续发生变化，表明它们持续参与耐药性。此外，在对新辅助化疗表现出病理完全缓解（pCR）的IBC患者（n = 87）的过表达基因中，与核糖体过程相关的基因显着富集（P < 0.001）。鉴于 IBC 肿瘤（包括 rSUM149）中 MAPK 常见的过度激活，我们在临床试验中评估了 Merestinib（一种多激酶抑制剂）。它有效靶向 pERK 和 peIF4E 通路，抑制下游靶点，诱导耐药 rSUM149 细胞死亡，并在亲代细胞中与另一种酪氨酸激酶抑制剂（拉帕替尼）表现出协同作用。这强调了它对蛋白质合成信号传导的重大影响，这对于对抗癌细胞的翻译依赖性至关重要。总之，我们的研究阐明了 IBC 细胞响应治疗和治疗暂停的适应性变化，指导针对这种具有挑战性的癌症类型的精准医学方法。© 2024。作者。

Therapeutic resistance presents a significant hurdle in combating inflammatory breast cancer (IBC), adding to the complexity of its management. To investigate these mechanisms, we conducted a comprehensive analysis using transcriptomic and proteomic profiling in a preclinical model alone with correlates of treatment response in IBC patients. This included SUM149 cell lines derived from treatment-naïve patients, along with acquired drug resistance (rSUM149) and others in a state of resistance reversal (rrSUM149), aiming to uncover drug resistance networks. We identified specific ribosomal proteins associated with acquiring resistance. These correlated with elevated levels of molecular markers such as pERK, CDK1, XIAP, and SOD2. While resistance reversal in rrSUM149 cells largely normalized the expression profile, VIPER analysis revealed persistent alterations in ribosomal process-related proteins (AGO2, Exportin 1, RPL5), suggesting their continued involvement in drug resistance. Moreover, genes linked to ribosomal processes were significantly enriched (P < 0.001) among overexpressed genes in IBC patients (n = 87) who exhibited a pathological complete response (pCR) to neoadjuvant chemotherapy. Given the common hyperactivation of MAPK in IBC tumors, including rSUM149, we evaluated Merestinib, a multikinase inhibitor in clinical trials. It effectively targeted pERK and peIF4E pathways, suppressed downstream targets, induced cell death in drug-resistant rSUM149 cells, and showed synergistic effects with another tyrosine kinase inhibitor (Lapatinib) in parental cells. This underscores its significant impact on protein synthesis signaling, crucial for combating translational dependence in cancer cells. In summary, our study elucidates adaptive changes in IBC cells in response to therapy and treatment pauses, guiding precision medicine approaches for this challenging cancer type.© 2024. The Author(s).