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

Background: 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.
Methods: 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).
Results: 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).
Conclusions: 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.
Competing Interests: Competing interests Dr O Engebraaten receives institutional research support from AstraZeneca. Dr A Kristian is currently an employee at Novartis. All other authors have no conflict of interest to report. Ethics approval Ethical approvals for the studies involving animals (FOTSid 10296, 12097/28802 and 15499) were given by the Norwegian Food Safety Authority. All experiments involving animals were carried out in accordance with institutional guidelines, national legislation, and the European Union Directive 2010/63/EU.
(© 2024. The Author(s).)