Challenges in Triple Negative Breast Cancer Treatment and Therapeutic Potential of the Mitogen Activated Protein Kinase Pathway

Triple negative breast cancer (TNBC) is the most aggressive breast cancer subtype, characterised by the lack of progesterone receptor, oestrogen receptor and HER2 expression, and is typically associated with high rates of metastasis, recurrence and mortality. Despite recent advances, such as the use of PARP inhibitors, immune checkpoint inhibitors and antibody-drug conjugates, lasting clinical benefit is limited, particularly in advanced disease. A key driver of relapse in TNBC is extensive inter- and intratumoral heterogeneity, largely sustained by self-renewing cancer stem cell (CSC) populations. These cells exhibit enhanced plasticity, immune evasion and resistance to cytotoxic drugs, enabling treatment failure and relapse. Growing evidence implicates aberrant activation of mitogen activated protein kinase (MAPK) signalling in CSC maintenance, epithelial-mesenchymal transition (EMT) and resistance to therapy in TNBC. While MAPK pathway inhibitors show limited efficacy in monotherapy, preclinical and clinical data suggest that their integration with existing treatment strategies may enhance therapeutic robustness, delay resistance and reduce recurrence. Targeting MAPK, in combination with other drugs that restrain CSC plasticity could represent a promising strategy to improve long-term outcomes in TNBC.