Identification of Src Family Kinases as Potential Therapeutic Targets for Chemotherapy-Resistant Triple Negative Breast Cancer

SIMPLE SUMMARY: Breast cancer remains the leading cause of cancer-related deaths in women worldwide. One particular subtype, triple negative breast cancer (TNBC), is known for being highly aggressive and metastatic, with a high prevalence of resistance to chemotherapy. Patients with chemotherapy-resistant TNBC tumors have virtually no treatment options. Here, we studied tyrosine phosphorylation-mediated signaling networks in chemotherapy-resistant TNBC xenografts, to identify potential therapeutic targets. We identified Src family kinases (SFK) as potential drug targets. Inhibition of SFKs radically reduced tumor growth in xenografts that had a signature of high SFK-activity. We assessed a small number of human tumor tissue specimens and found a low prevalence of SFK-driven tumors. These data may explain the previous unsuccessful clinical trials targeting SFKs in TNBC and warrant further studies with a higher number of patient samples. These results emphasize the importance of the characterization of phosphotyrosine signaling profiles for better patient stratification, in addition to gaining novel therapeutic insights. ABSTRACT: Neoadjuvant chemotherapy (NAC) remains the cornerstone of the treatment for triple negative breast cancer (TNBC), with the goal of complete eradication of disease. However, for patients with residual disease after NAC, recurrence and mortality rates are high and the identification of novel therapeutic targets is urgently needed. We quantified tyrosine phosphorylation (pTyr)-mediated signaling networks in chemotherapy sensitive (CS) and resistant (CR) TNBC patient-derived xenografts (PDX), to gain novel therapeutic insights. The antitumor activity of SFK inhibition was examined in vivo. Treated tumors were further subjected to phosphoproteomic and RNAseq analysis, to identify the mechanism of actions of the drug. We identified Src Family Kinases (SFKs) as potential therapeutic targets in CR TNBC PDXs. Treatment with dasatinib, an FDA approved SFK inhibitor, led to inhibition of tumor growth in vivo. Further analysis of post-treatment PDXs revealed multiple mechanisms of actions of the drug, confirming the multi-target inhibition of dasatinib. Analysis of pTyr in tumor specimens suggested a low prevalence of SFK-driven tumors, which may provide insight into prior clinical trial results demonstrating a lack of dasatinib antitumor activity in unselected breast cancer patients. Taken together, these results underscore the importance of pTyr characterization of tumors, in identifying new targets, as well as stratifying patients based on their activated signaling networks for therapeutic options. Our data provide a strong rationale for studying SFK inhibitors in biomarker-selected SFK-driven TNBC.