Targeting of a novel interplay between MET tyrosine kinase and NRF2 enhances sensitivity to Paclitaxel in triple negative breast cancer

Abstract Background Triple-negative breast cancer (TNBC) is a very aggressive and heterogeneous cancer. The lack of effective targeted therapies and the frequency of relapses point to the urgent need to identify molecular vulnerabilities to overcome resistance to chemotherapy. Nuclear Factor Erythroid 2-related factor 2 (NRF2) is a transcription factor that plays a central role in response to oxidative stress. Its hyperactivation contributes to metabolic rewiring and resistance to therapy in several tumours including TNBC. Efficient pharmacological approaches that block NRF2 functions are still missing. Protein Tyrosine Kinases (PTKs), often overactivated in cancer and influencing several signalling pathways, are promising candidates to explore for their potential impact on NRF2. Methods The link between Receptor Tyrosine Kinases (RTKs) and NRF2 expression and its impact on the survival probability of TNBC and non-TNBC patients were investigated by bioinformatic analyses using TCGA and GEO databases. MET-NRF2 connection was further confirmed by immunoblotting, immunofluorescence, RT-qPCR, and RNAseq experiments through the combinatorial use of murine and human TNBC cellular models. The efficacy of combination treatments with Paclitaxel and specific inhibitors of MET-NRF2 signalling was assessed by viability assays and flow-cytometry analyses on TNBC cellular models as well as on TNBC patient-derived organoids. Results Here, we identify a novel interplay between MET and SRC kinases with NRF2 expression and activity and demonstrate that its targeting enhances the sensitivity to the standard Paclitaxel treatment of TNBC cells and patient-derived organoids. Conclusions Our study shows that RTKs regulate NRF2 expression and activation in TNBC providing a proof of principle for the ability of Tyrosine Kinase Inhibitors (TKIs) to impinge on NRF2 signalling. Our findings also uncover the value of the MET-SRC-NRF2 axis as exploitable vulnerability in NRF2-hyperactivated TNBC, paving the way for the repositioning of TKIs as modulators of NRF2 signalling.