Breast cancer characteristics can predict treatment responses and patient outcomes. Treatment decisions are based on the expression of three hormonal receptors: ER, PR and HER2. Hormonal therapies are the mainstay treatment for hormone responsive breast cancer patients, while chemotherapy is the only option for patients with hormone receptor negative tumours. Key challenges are to identify new drugs that are efficacious with fewer undesirable side effects, and to match them with the subtype of breast cancer that will respond.
Smac-mimetics block Inhibitor of APoptosis (IAP) protein function, resulting in cancer cell death. Using patient-derived xenograft (PDX) models, we evaluated the efficacy of the clinical candidate smac-mimetic birinapant on different subtypes of breast cancer. We found a differential sensitivity to birinapant amongst breast cancer subtypes. The Triple Negative Breast Cancers (TNBC) were more sensitive to birinapant compare to ER+ breast cancers. Birinapant killing in TNBC was dependent on TNF, TRAIL and caspases activation. Transcriptomic analysis using the TCGA database revealed that the expression of genes encoding positive regulators of smac-mimetic killing were higher in TNBC in comparison to ER+ breast cancers. Our study demonstrated that a ‘smac-mimetic gene signature’ could be used to predict responsiveness to smac-mimetic and that ER+ expression is responsible for smac-mimetic resistance. Importantly, we showed that the combination of birinapant with chemotherapy was superior to chemotherapy alone in the treatment of TNBC PDX in vivo. Altogether our study provides the rational for the clinical evaluation of smac-mimetic in therapy for TNBC.