对化疗的耐药性加上耐药肿瘤之间的异质性，对三阴性乳腺癌（TNBC）的临床治疗构成了重大挑战。通过剖析与治疗耐药性相关的分子途径，我们试图定义患者亚组和下一线治疗的可行目标。对代表紫杉醇敏感的同基因患者来源的异种移植物 (PDX) 进行批量 RNA 测序和反相蛋白阵列分析和耐药肿瘤。在耐药模型中鉴定为上调的途径作为 PDX 外植体中的靶标进行了进一步探索。在两个不同的患者队列（NeoAva 和 MET500）中评估了它们的临床相关性。在治疗耐药性 PDX 中发现涉及 SRC 家族激酶 (SFK) 和 MAPK/ERK 的信号通路活性增加，靶向抑制剂在耐药性中显着更有效肿瘤。在新辅助治疗后的化疗耐药患者亚组中也检测到 SFK 和 MAPK/ERK 通路上调。此外，在疾病快速进展的 TNBC 患者（中位无病间隔 27 个月与 105 个月）的转移灶中检测到高 SFK 表达（SRC、FYN 和/或 YES1）。在一个子集中发现了 SFK 信号传导的上调化疗耐药性肿瘤，并且在转移性病变中持续存在。根据临床前结果，这些患者可能会对针对 SFK 的治疗产生良好反应。© 2024。作者。

Resistance to chemotherapy, combined with heterogeneity among resistant tumors, represents a significant challenge in the clinical management of triple negative breast cancer (TNBC). By dissecting molecular pathways associated with treatment resistance, we sought to define patient sub-groups and actionable targets for next-line treatment.Bulk RNA sequencing and reverse phase protein array profiling were performed on isogenic patient-derived xenografts (PDX) representing paclitaxel-sensitive and -resistant tumors. Pathways identified as upregulated in the resistant model were further explored as targets in PDX explants. Their clinical relevance was assessed in two distinct patient cohorts (NeoAva and MET500).Increased activity in signaling pathways involving SRC-family kinases (SFKs)- and MAPK/ERK was found in treatment resistant PDX, with targeted inhibitors being significantly more potent in resistant tumors. Up-regulation of SFKs- and MAPK/ERK-pathways was also detected in a sub-group of chemoresistant patients after neoadjuvant treatment. Furthermore, High SFK expression (of either SRC, FYN and/or YES1) was detected in metastatic lesions of TNBC patients with fast progressing disease (median disease-free interval 27 vs 105 months).Upregulation of SFK-signaling is found in a subset of chemoresistant tumors and is persistent in metastatic lesions. Based on pre-clinical results, these patients may respond favorably to treatment targeting SFKs.© 2024. The Author(s).