Current standard of care for triple negative breast cancer (TNBC) is chemotherapy. However, about 25% of patients are either intrinsically chemorefractory or acquire resistance following chemotherapy. Multiple receptor tyrosine kinases (RTKs) can drive aggressiveness in cancer, and many treatment-naïve TNBCs already have elevated levels of activated RTKs - with RTK activation playing a role in several forms of targeted therapy resistance. However, the combination of RTKs that contribute to resistance varies between patients and between treatment regimens. This degree of heterogeneity hampers the use of RTK-targeting drugs as these mostly target one or a select few RTKs, and so there is a high failure rate of single RTK-targeted therapy. We propose a novel approach to overcome treatment resistance in TNBC patients who have activated RTKs driven by a specific tyrosine-phosphorylated form of PKCδ.
We have discovered that about 25-30% of TNBC patients have high levels of a novel activated form of PKCδ that is phosphorylated on Y374 (pY374-PKCδ). We find that elevated levels of pY374-PKCδ correlate with (1) increased detection of a RAB5-Rab7 double positive endosomal compartment, (2) enhanced recycling and reduced degradation of multiple internalised RTKs, and (3) increased anchorage independent growth in breast cancer cells in vitro. In a cohort of TNBC patients, we found that around a third displayed both elevated pY374-PKCδ and RAB5-Rab7 double positive endosomes, suggesting that these patients may have dysregulated RTK trafficking. We hypothesise that, in TNBC patients with high pY374-PKCδ, downregulating phosphorylation of Y374-PKCδ represents a novel treatment strategy that could (1) reduce oncogenic signalling without needing to identify the specific activated RTK(s) involved, and (2) reduce the likelihood of resistance through compensatory signalling by other RTKs, as occurs with single RTK-targeted therapies.