Triple negative breast cancer (TNBC) is difficult to treat due to lack of druggable targets. We have found that treatment with the small molecule inhibitor KPT-9274 inhibits growth of TNBC cells and eventually leads to cell death. KPT-9274 is a dual specific inhibitor of PAK4 and Nicotinamide Phosphoribosyltransferase (NAMPT). The PAK4 protein kinase is often highly expressed in TNBC cells and has important roles in cell growth, survival, and migration. Previously we have found that inhibition of PAK4 leads to growth inhibition of TNBC cells both in vitro and in vivo. Likewise, NAMPT has been shown to be dysregulated in cancer due to its role in cell metabolism. In order to understand better how treating cells with KPT-9274 abrogates TNBC cell growth, we carried out an RNA sequencing of TNBC cells treated with KPT-9274. As a result, we identified Rictor as an important target that is inhibited in the KPT-9274 treated cells. Conversely, we found that Rictor is predicted to be activated when PAK4 is overexpressed in cells, which suggests a role for PAK4 in the regulation of Rictor. Rictor is a component of mTORC2, one of the complexes formed by the serine/threonine kinase mTOR. mTOR is important for the control of cell growth and metabolism. Our results suggest a new mechanism by which the KPT-9274 compound may block the growth of breast cancer cells, which is via inhibition of mTORC2 signaling. Consistent with this, sequencing analysis of PAK4 overexpressing cells indicates that PAK4 has a role in activation of the mTOR pathway.

Mammalian cells have the ability to respond to a myriad of diverse extracellular stimuli that modulate cell function. This often involves ligands binding to cell surface receptors and subsequent activation of intracellular signaling pathways. These pathways can lead to changes in gene expression patterns that in turn regulate cell growth, differentiation, migration, and function. One important type of cell surface receptor is the receptor tyrosine kinase (RTK). In response to in response to ligand binding, RTKs dimerize, then trans-phosphorylate each other, leading to activation of downstream pathways. While the signaling proteins in these pathways are important for normal cell growth control, when improperly regulated they can lead to uncontrolled growth and sometimes cancer. For this reason, they are often considered to be good candidates for drug targets for chemotherapeutic drugs. RTKs can activate multiple different signaling pathways. Some of the signaling proteins in these pathways can have crosstalk with other RTK activated pathways, and some of them can be activated by multiple mechanisms in addition to activation by RTKs. While there is a wide array of different signaling proteins and pathways activated by RTKs, in this review we will discuss components of several key pathways including the MAPK pathway, the Her2/Neu pathway, mTOR, and Pak kinases. We provide an overview of the roles for these pathways in cell signaling and discuss how different components of these pathways are being considered as targets for cancer treatment.