AI Article Synopsis
- Triple negative breast cancer (TNBC) poses treatment challenges due to chemotherapy resistance and tumor diversity, prompting researchers to identify molecular pathways and patient sub-groups for targeted therapies.
- Using RNA sequencing and reverse phase protein analysis on patient-derived xenografts, the study discovered that signaling pathways like SRC-family kinases (SFKs) and MAPK/ERK are more active in chemotherapy-resistant tumors, indicating potential targets for treatment.
- High expression of these pathways correlates with poor outcomes in some TNBC patients, suggesting that those with elevated SFK levels, particularly in metastatic lesions, could benefit from future SFK-targeted therapies.
Article Abstract
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.
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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC11554838 | PMC |
| http://dx.doi.org/10.1038/s41416-024-02875-5 | DOI Listing |
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