Development of novel multimodality radiotherapy treatments in metastatic breast cancer, especially in the most aggressive triple negative (TNBC) subtype, is of significant clinical interest. Here we show that a novel inhibitor of Polo-Like Kinase 4 (PLK4), CFI-400945, in combination with radiation, exhibits a synergistic anti-cancer effect in TNBC cell lines and patient-derived organoids in vitro and leads to a significant increase in survival to tumor endpoint in xenograft models in vivo, compared to control or single-agent treatment. Further preclinical and proof-of-concept clinical studies are warranted to characterize molecular mechanisms of action of this combination and its potential applications in clinical practice.

Breast cancer remains a leading cause of mortality among women worldwide. Brain metastases confer extremely poor prognosis due to a lack of understanding of their specific biology, unique physiologic and anatomic features of the brain, and limited treatment strategies. A major roadblock in advancing the treatment of breast cancer brain metastases (BCBM) is the scarcity of representative experimental preclinical models. Current models are predominantly based on the use of animal xenograft models with immortalized breast cancer cell lines that poorly capture the disease’s heterogeneity. Recent years have witnessed the development of patient-derived in vitro and in vivo breast cancer culturing systems that more closely recapitulate the biology from individual patients. These advances led to the development of modern patient-tissue-based experimental models for BCBM. The success of preclinical models is also based on the imaging technologies used to detect metastases. Advances in animal brain imaging, including cellular MRI and multimodality imaging, allow sensitive and specific detection of brain metastases and monitoring treatment responses. These imaging technologies, together with novel translational breast cancer models based on patient-derived cancer tissues, represent a unique opportunity to advance our understanding of brain metastases biology and develop novel treatment approaches. This review discusses the state-of-the-art knowledge in preclinical models of this disease.

Resistance to protein tyrosine kinase inhibitors (TKIs) presents a significant challenge in therapeutic target development for cancers such as triple-negative breast cancer (TNBC), where conventional therapies are ineffective at combatting systemic disease. Due to increased expression, the receptor tyrosine kinases EGFR (epidermal growth factor receptor) and c-Met are potential targets for treatment. However, targeted anti-EGFR and anti-c-Met therapies have faced mixed results in clinical trials due to acquired resistance. We hypothesize that adaptive responses in regulatory kinase networks within the EGFR and c-Met signaling axes contribute to the development of acquired erlotinib and cabozantinib resistance. To test this, we developed two separate models for cabozantinib and erlotinib resistance using the MDA-MB-231 and MDA-MB-468 cell lines, respectively. We observed that erlotinib- or cabozantinib-resistant cell lines demonstrate enhanced cell proliferation, migration, invasion, and activation of EGFR or c-Met downstream signaling (respectively). Using a SILAC (Stable Isotope Labeling of Amino acids in Cell Culture)-labeled quantitative mass spectrometry proteomics approach, we assessed the effects of erlotinib or cabozantinib resistance on the phosphoproteome, proteome, and kinome. Using this integrated proteomics approach, we identified several potential kinase mediators of cabozantinib resistance and confirmed the contribution of AKT1 to erlotinib resistance in TNBC-resistant cell lines.