Mutations of p53 and BRAF also seem to not be correlated with sensitivity of BEZ235, because both sensitive and less sensitive cell lines harbor the mutations. Exploration of genetic changes of mTOR, the major target of BEZ235, might someday provide information that may predict therapeutic efficacy. Inhibition of mTORC1 may activate the MAPK pathway through a PI3K-dependent feedback loop, which explains why BEZ235 was seen here to activate ERK1/2 in thyroid cancer cells. Combining BEZ235 with an inhibitor targeting MAPK pathway may be a potential approach to enhance therapeutic efficacy. Recently, the combination of a pan-RAF inhibitor and BEZ235 was shown to induce cell cycle arrest at G0/G1 phase, and had beneficial combination effects in treating thyroid cancer. Similarly, in combination of mTOR and MEK inhibitors also demonstrated therapeutic advantage in treating thyroid cancer, providing further evidence that targeting both PI3K/ mTOR and MAPK pathways is a potential therapeutic strategy for this disease. Approximately 30% of humans are Staphylococcus aureus carriers without symptoms. S. aureus is also one of the most common pathogens in biofilm related infections of indwelling medical devices which are responsible for billions in healthcare cost each year in the United States. Bacteria can attach to the surface of biomaterials or tissues and form a multilayered structure consisting of bacterial cells enclosed in an extracellular polymeric matrix. Bacteria in biofilm are particularly resistant to antibiotic treatment. In addition to the difficulty of effectively inhibiting biofilm with conventional antibiotic therapy, treatment is further complicated by the rise of antibiotic resistance among BYL719 PI3K inhibitor staphylococci. In recent years, methicillin resistance in S. aureus is approaching an epidemic level. The emergence of antibiotic resistance poses an urgent medical problem worldwide. Current antibiotics target a small set of proteins essential for bacterial survival. As a result, antibiotic resistant strains are subjected to a strong positive selection pressure. Inappropriate and excessive use of antibiotics have contributed to the emergence of pathogens that are highly resistant to most currently available antibiotics. The novel approach of inhibiting pathogen virulence while minimizing the selection pressure for resistance holds great promise as an alternative to traditional antibiotic treatment. The feasibility of such an approach was demonstrated for Vibrio cholerae infections when a novel small molecule was identified that prevented the production of two critical virulence factors, cholera toxin and the toxin coregulated pilus. Administration of this compound in vivo protected infant mice from V. cholerae. In a similar proof-ofconcept study, a small molecule inhibitor of the membraneembedded sensor histidine kinase QseC was identified. The inhibitor exhibited in vivo protection of mice against infection by Salmonella typhimurium and Francisella tularensis. In a POC study following the same paradigm, we have identified a chemical series of small molecules from a high throughput screen that can inhibit expression of the streptokinase gene in group A streptococcus. We previously demonstrated that SK is a key virulence factor for GAS infection. SK activates human plasminogen into an active serine protease that degrades Evofosfamide fibrin.