Irreversible TrxR1 inhibitors block STAT3 activity and induce cancer cell death.

Because of its key role in cancer development and progression, STAT3 has become an attractive target for developing new cancer therapeutics. While several STAT3 inhibitors have progressed to advanced stages of development, their underlying biology and mechanisms of action are often more complex than would be expected from specific binding to STAT3. Here, we have identified and optimized a series of compounds that block STAT3-dependent luciferase expression with nanomolar potency. Unexpectedly, our lead compounds did not bind to cellular STAT3 but to another prominent anticancer drug target, TrxR1. We further identified that TrxR1 inhibition induced Prx2 and STAT3 oxidation, which subsequently blocked STAT3-dependent transcription. Moreover, previously identified inhibitors of STAT3 were also found to inhibit TrxR1, and likewise, established TrxR1 inhibitors block STAT3-dependent transcriptional activity. These results provide new insights into the complexities of STAT3 redox regulation while highlighting a novel mechanism to block aberrant STAT3 signaling in cancer cells.

IL-6 activated JAK/STAT3 pathway and sensitivity to Hsp90 inhibitors in multiple myeloma.

Modern anti-cancer treatment involves targeted therapy that aims at inactivating particular oncoproteins or signaling pathways in a cancer-type-specific manner. A number of potent targeted therapies affecting oncogenic kinases or receptor tyrosine kinases have revolutionized anti-cancer treatment. These drugs inactivate signaling pathways that cancer cells depend on and therefore inhibit their proliferation and survival. Molecular chaperones of the Hsp90 family (heat shock protein 90) support the integrity, folding and function of many proteins involved in proliferation, survival, DNA damage and repair. Hsp90 proteins are thus required to maintain activity of a large variety of oncogenic proteins, including members of the JAK/STAT and the PI3K pathways. Accordingly cancer cells rely on Hsp90 proteins and their expression is often elevated in malignant cells. In line with this, inhibitors of Hsp90 (Hsp90-Is) have demonstrated potent antitumor activity in preclinical studies. While Hsp90-Is can be considered as targeted therapy, their broad effects on multiple signaling pathways make it difficult to predict the therapeutic outcome. Multiple myeloma (MM) is one of the tumor types with elevated Hsp90 levels. Hsp90-Is demonstrated promising activity in preclinical studies of MM and in several clinical trials. However, large variability in response questioned the use of Hsp90-Is as single drugs in the treatment of myeloma. A critical factor in targeted therapies, including Hsp90-Is, is identification of susceptible subgroups of patients. Predictive biomarkers in each particular tumor type are important in order to use anti-cancer drugs in a rational way. Interestingly, levels of Hsp90 expression has not proven to be decisive for treatment response and hence stratification of myeloma patients. Others and we have recently found that MM cells with an IL-6-activated JAK/STAT3 pathway are particularly sensitive to Hsp90-Is. In this review we will discuss these findings, both in terms of molecular mechanisms and applications for selection of MM patients amenable to Hsp90-I treatment in an individually targeted treatment strategy.