NOTCH3 inactivation increases Triple Negative Breast Cancer sensitivity to gefitinib by promoting EGFR tyrosine dephosphorylation and its intracellular arrest.

Triple-negative breast cancer (TNBC) accounts for about 15-20% of breast cancers and represents the most aggressive subtype (1). To date, no molecularly targeted agents are approved for TNBC, leading to the conventional chemotherapy the role of primary option for systemic treatment. Therefore, effective therapeutic strategies for TNBC are urgently needed. The tyrosine kinase receptor EGFR overexpression is a hallmark of TNBC. Anti-EGFR therapies, including EGFR inhibitors, are not currently approved for breast cancer treatment, since the results from clinical trials are disappointing (2) due to the existence of compensatory pathways that confer resistance to EGFR inhibition. Notch signaling dysregulation is often associated with the pathogenesis and progression of TNBC (3). In addition, Notch-EGFR interplay occurs in breast cancer (4), raising the possibility that Notch signalling could be involved in the resistance to EGFR inhibition. Consequently, the combined Notch-EGFR pathway inhibition, in this context, is a potential therapeutic approach for overcoming resistance to drugs (5). Pan-Notch inhibition using gamma-secretase-inhibitors (GSIs) treatment supports this conclusion but it fails to distinguish the particular Notch receptor which drives growth. Therefore, it is relevant to investigate which is the main Notch receptor involved in the resistance to EGFR inhibition in order to understand the main strategy for TNBC cancer therapy. It has been demonstrated that constitutive Notch3 signalling can drive an oncogenic program in a subset of TNBCs, thus suggesting that Notch3 activity, and not others Notch paralogues, may be relevant in this breast cancer subtype (6).