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

• Published in: British journal of cancer Vol. 131; no. 10; pp. 1656 - 1667
• Main Authors: Egeland, Eivind Valen, Seip, Kotryna, Skourti, Eleni, Øy, Geir Frode, Pettersen, Solveig J., Pandya, Abhilash D., Dahle, Maria A., Haugen, Mads H., Kristian, Alexander, Nakken, Sigve, Engebraaten, Olav, Mælandsmo, Gunhild M., Prasmickaite, Lina
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 30.11.2024; Nature Publishing Group; Springer Nature
• Subjects: 631/67/1059; 631/67/1347; 631/67/1857; 631/67/70; Animals; Biomedical and Life Sciences; Biomedicine; Breast cancer; Cancer Research; Cancer therapies; Chemotherapy; Disease management; Drug Resistance; Drug Resistance, Neoplasm; Epidemiology; Explants; Female; Fyn protein; Humans; Kinases; MAP kinase; MAP Kinase Signaling System - drug effects; Metastases; Metastasis; Mice; Molecular Medicine; Oncology; Paclitaxel; Paclitaxel - pharmacology; Paclitaxel - therapeutic use; Patients; Protein arrays; Signal transduction; Signal Transduction - drug effects; Src protein; src-Family Kinases - antagonists & inhibitors; src-Family Kinases - metabolism; Therapeutic targets; Treatment resistance; Triple Negative Breast Neoplasms - drug therapy; Triple Negative Breast Neoplasms - genetics; Triple Negative Breast Neoplasms - pathology; Tumors; Up-regulation; Xenograft Model Antitumor Assays
• ISSN: 0007-0920; 1532-1827; 1532-1827
• DOI: 10.1038/s41416-024-02875-5

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.