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.