Department of Tumor Biology, Institute for Cancer Research, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway.
Insitute for Clinical Medicine, University of Oslo, Oslo, Norway.
Br J Cancer. 2024 Nov;131(10):1656-1667. doi: 10.1038/s41416-024-02875-5. Epub 2024 Oct 10.
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.
化疗耐药性，加上耐药肿瘤的异质性，是三阴性乳腺癌（TNBC）临床治疗的重大挑战。通过剖析与治疗耐药相关的分子通路，我们试图确定患者亚组和下一阶段治疗的可行靶点。
对代表紫杉醇敏感和耐药的同基因患者衍生异种移植物（PDX）进行了批量 RNA 测序和反相蛋白阵列分析。在耐药模型中上调的通路被进一步探索为 PDX 外植体的靶点。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。
在治疗耐药的 PDX 中发现涉及 SRC 家族激酶（SFKs）和 MAPK/ERK 的信号通路活性增加，靶向抑制剂在耐药肿瘤中更有效。在新辅助治疗后，化疗耐药患者中也检测到 SFKs 和 MAPK/ERK 通路的上调。此外，在疾病进展迅速的 TNBC 患者的转移性病变中检测到高 SFK 表达（SRC、FYN 和/或 YES1 中的任意一种）（中位无疾病间隔 27 与 105 个月）。
在一部分化疗耐药肿瘤中发现 SFK 信号通路的上调，并且在转移性病变中持续存在。基于临床前结果，这些患者可能对靶向 SFKs 的治疗有良好的反应。
