Sensitization to Carboplatin Chemotherapy by Decoding Intra Tumor Heterogeneity in Triple Negative Breast Cancer

Triple negative breast cancer (TNBC) lacks known biomarkers for targeted therapy. TNBC is highly resistant to cytotoxic chemotherapeutic drugs such as carboplatin and often relapse post treatment. One of the main reasons for the development of drug resistance is intra-tumor heterogeneity. To decipher this heterogeneity, we examine protein expression levels of central biomarkers in hundreds of thousands of individual TNBC cells. Identification and characterization of such subpopulation/s that expand/s in response to chemotherapy, thereby causing the pro-survival phenotype, will allow us to predict a targeted therapy that will optimize the tumor response to chemotherapy.

Cells were examined for differential expression of 11 biomarkers using multicolor flow cytometry (FACS) followed by informational-theoretical single cell surprisal analysis. This computational development allows quantifying a set of unbalanced processes in each individual cell, named cell specific signaling signature (CSSS), and then mapping distinct subpopulations in every tumor responding to an outside influence.

CSSS analysis revealed that two distinct subpopulations evolved within TNBC populations in response to carboplatin. These subpopulations harbored ALDH1+ (aldehyde dehydrogenase 1) and c-MET+ (mesenchymal-epithelial transition factor) ongoing processes. In-vitro validation showed that only simultaneous targeting of ALDH1 and c-Met was successful in sensitizing TNBC to carboplatin chemotherapy and preventing its regrowth. The experiments are underway to validate our approach using patient-derived TNBC tumors in-vivo.

Our preliminary results suggest that the CSSS approach significantly enhances tumor response to carboplatin and prevents regrowth of once resistant TNBC tumors.