Anti-PIK3R1 monoclonal antibody, clone U5

Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer with poor clinical prognosis and limited targeted treatment strategies. Kinase inhibitor screening of a panel of 20 TNBC cell lines uncovered three critical TNBC subgroups: 1) sensitive to only MEK inhibitors; 2) sensitive to only Akt inhibitors; 3) resistant to both MEK/Akt inhibitors. Using genomic, transcriptomic and proteomic datasets of these TNBC cell lines we unravelled molecular features associated with the MEK and Akt drug resistance. MEK inhibitor-resistant TNBC cell lines were discriminated from Akt inhibitor-resistant lines by the presence of PIK3CA/PIK3R1/PTEN mutations, high p-Akt and low p-MEK levels, yet these features could not distinguish double-resistant cells. Gene set enrichment analyses of transcriptomic and proteomic data of the MEK and Akt inhibitor response groups revealed a set of cell cycle-related genes associated with the double-resistant phenotype; these genes were overexpressed in a subset of breast cancer patients. CDK inhibitors targeting the cell cycle programme could overcome the Akt and MEK inhibitor double-resistance. In conclusion, we uncovered molecular features and alternative treatment strategies for TNBC that are double-resistant to Akt and MEK inhibitors.

Osteoarthritis (OA) is a degenerative disease characterized by deterioration of articular cartilage. Recent studies have demonstrated the importance of some microRNAs in cartilage damage. The aim of this study was to identify and characterize the expression of microRNA-634 (miR-634) in normal and OA chondrocytes, and to determine its role in OA pathogenesis. Human normal and OA chondrocytes obtained from patients were cultured in vitro. Transfection with miR-634 mimic or inhibitor was employed to investigate the effect of miR-634 on chondrocyte survival and matrix synthesis, and to identify miR-634 target. The results indicated that miR-634 was expressed at lower level in high grade OA chondrocyte compared with normal chondrocytes. Overexpression of miR-634 could inhibit cell survival and matrix synthesis in high grade OA chondrocytes. Furthermore, miR-634 targeted PIK3R1 gene that encodes the regulatory subunit 1 of class I PI3K (p85 alpha) and exerted its inhibitory effect on the phosphorylation of Akt, mTOR, and S6 signal molecules in high grade OA chondrocytes. Therefore, the data suggested that miR-634 could suppress survival and matrix synthesis of high grade OA chondrocytes through targeting PIK3R1 gene to modulate the PI3K/Akt/S6 and PI3K/Akt/mTOR/S6 axes, with important implication for validating miR-634 as a potential target for OA therapy.