SRC家庭用作三重阴性乳腺癌的治疗靶标，具有对化学疗法的耐药性
The SRC-family serves as a therapeutic target in triple negative breast cancer with acquired resistance to chemotherapy
影响因子:6.80000
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
摘要
抗化疗的耐药性以及抗性肿瘤之间的异质性，代表了三乳腺癌（TNBC）临床管理的重大挑战。通过解剖与治疗耐药性相关的分子途径，我们试图定义患者亚组和可行的次线治疗靶标。BulkRNA测序和反相蛋白阵列分析是对代表紫杉醇敏感的和 - 敏感的敏感性和 - 抗抑制剂的同源性患者衍生的异种移植物（PDX）进行的。在PDX外植体中，进一步探讨了在抗性模型中被确定为上调的途径。在两个不同的患者队列中评估了它们的临床相关性。在新辅助治疗后，在一组化学耐药性患者中也检测到SFKS和MAPK/ERK通道的上调。此外，在TNBC患者的转移性病变中检测到高SFK表达（SRC，FYN和/或YES1）。基于临床前结果，这些患者可能对针对SFK的治疗方法有利。
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.