Triple negative breast cancer (TNBC) represents a challenging clinical entity due to its aggressive nature, high propensity for recurrence and metastasis. There are currently limited treatment options. In the absence of targeted therapies, the prognosis for TNBC patients following chemotherapy failure remains bleak, with an average survival period of approximately 12 months. The heterogeneous characteristics of TNBC, coupled with the absence of reliable biomarkers for predicting chemoresistance, have impeded the development of effective targeted therapies.
Our research has unveiled a promising avenue for combating chemoresistance in TNBC by focusing on the hyperphosphorylation of Y374 on PKCδ, which is observed in a subset of TNBC cells. We have identified that TNBC cells exhibiting hyperphosphorylation of Y374-PKCδ possess 'persister' cell properties that eventually give rise to a chemoresistant cell population, demonstrating increased tolerance to chemotherapeutic agents. Importantly, we have shown that inhibiting the phosphorylation of Y374-PKCδ can reverse this chemoresistant phenotype.
Through virtual screening, we have identified a panel of small compounds with molecular masses below 800 Da that have the potential to bind to an allosteric pocket on PKCδ, thereby obstructing the phosphorylation of Y374 and reducing the levels of pY374-PKCδ. Experimental validation of these compounds has validated their ability to inhibit the phosphorylation of Y374-PKCδ in TNBC cells, offering promising evidence for the feasibility of this approach.
Crucially, our findings indicate that the identified compounds do not function as ATP-dependent kinase inhibitors, ensuring selective targeting of Y374 phosphorylation without interfering with the canonical kinase activity of PKCδ. Using surface plasmon resonance (SPR) and microscale thermophoresis (MST) we have confirmed the direct binding of these compounds to PKCδ, underscoring their potential as targeted therapeutics for TNBC.
In conclusion, our research highlights the therapeutic potential of targeting Y374-PKCδ phosphorylation in overcoming chemoresistance in TNBC. By elucidating the mechanisms underlying this novel strategy, we pave the way for the development of precision therapies that can enhance treatment outcomes and improve survival rates for TNBC patients.