Kinome rewiring reveals AURKA limits PI3K-pathway inhibitor efficacy in breast cancer.

Dysregulation of the PI3K-AKT-mTOR signaling network is a prominent feature of breast cancers. However, clinical responses to drugs targeting this pathway have been modest, possibly because of dynamic changes in cellular signaling that drive resistance and limit drug efficacy. Using a quantitative chemoproteomics approach, we mapped kinome dynamics in response to inhibitors of this pathway and identified signaling changes that correlate with drug sensitivity. Maintenance of AURKA after drug treatment was associated with resistance in breast cancer models. Incomplete inhibition of AURKA was a common source of therapy failure, and combinations of PI3K, AKT or mTOR inhibitors with the AURKA inhibitor MLN8237 were highly synergistic and durably suppressed mTOR signaling, resulting in apoptosis and tumor regression in vivo. This signaling map identifies survival factors whose presence limits the efficacy of targeted therapies and reveals new drug combinations that may unlock the full potential of PI3K-AKT-mTOR pathway inhibitors in breast cancer

Clinical application of scaffolds for cartilage tissue engineering

The purpose of this paper is to review the basic science and clinical literature on scaffolds clinically available for the treatment of articular cartilage injuries. The use of tissue-engineered grafts based on scaffolds seems to be as effective as conventional ACI clinically. However, there is limited evidence that scaffold techniques result in homogeneous distribution of cells. Similarly, few studies exist on the maintenance of the chondrocyte phenotype in scaffolds. Both of which would be potential advantages over the first generation ACI. The mean clinical score in all of the clinical literature on scaffold techniques significantly improved compared with preoperative values. More than 80% of patients had an excellent or good outcome. None of the short- or mid-term clinical and histological results of these tissue-engineering techniques with scaffolds were reported to be better than conventional ACI. However, some studies suggest that these methods may reduce surgical time, morbidity, and risks of periosteal hypertrophy and post-operative adhesions. Based on the available literature, we were not able to rank the scaffolds available for clinical use. Firm recommendations on which cartilage repair procedure is to be preferred is currently not known on the basis of these studies. Randomized clinical trials and longer follow-up periods are needed for more widespread information regarding the clinical effectiveness of scaffold-based, tissue-engineered cartilage repair