SRC家族作为三阴性乳腺癌获得耐药后的治疗靶点

The SRC-family serves as a therapeutic target in triple negative breast cancer with acquired resistance to chemotherapy

BRITISH JOURNAL OF CANCER

影响因子:6.8

分区:医学2区 Top / 肿瘤学2区

发表日期:2024 Nov

作者: Eivind Valen Egeland, Kotryna Seip, Eleni Skourti, Geir Frode Øy, Solveig J Pettersen, Abhilash D Pandya, Maria A Dahle, Mads H Haugen, Alexander Kristian, Sigve Nakken, Olav Engebraaten, Gunhild M Mælandsmo, Lina Prasmickaite

DOI: 10.1038/s41416-024-02875-5

摘要

耐药性及其在耐药肿瘤中的异质性是临床管理三阴性乳腺癌（TNBC）的重大挑战。通过解析与耐药相关的分子通路，我们旨在定义患者亚组及下一线治疗的潜在靶点。对代表紫杉醇敏感和耐药肿瘤的同源患者来源异种移植物（PDX）进行整体RNA测序和逆相蛋白质阵列分析。鉴定出在耐药模型中上调的信号通路，进一步在PDX外植体中探索为潜在靶点。其临床相关性在两个不同的患者队列（NeoAva和MET500）中进行评估。在耐药PDX中发现涉及SFKs（SRC家族激酶）和MAPK/ERK的信号通路活性增强，靶向抑制剂在耐药肿瘤中表现出更强的效力。在新辅助治疗后，一些化疗耐药患者的SFKs和MAPK/ERK通路也显示上调。此外，在快速进展的TNBC患者的转移病灶中检测到高SFK表达（包括SRC、FYN和/或YES1），中位无病生存期为27个月对比105个月。SFK信号的上调在一部分化疗耐药肿瘤中持续存在，且在转移灶中仍然显著。基于前临床结果，这些患者可能对靶向SFK的治疗反应良好。

Abstract

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.