About 15-20% of breast cancers are Triple negative (TNBC), a devastating disease with limited therapeutic options. A recent phase 2 clinical trial testing AKT inhibitor ipatasertib (IPAT) plus paclitaxel in TNBC has produced promising results. However, the PI3k-based markers (based on current knowledge) surprisingly failed to predict IPAT response. We discovered that MAPK4 activation provides an alternative pathway for AKT activation that is completely independent of the PI3K pathway. Currently, there is no MAPK4-specific inhibitor (although we have started to screen for one). However, our preliminary results suggest that MAPK4 activation of AKT is essential for growth of MAPK4-high TNBC can...

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About 15-20% of breast cancers are Triple negative (TNBC), a devastating disease with limited therapeutic options. A recent phase 2 clinical trial testing AKT inhibitor ipatasertib (IPAT) plus paclitaxel in TNBC has produced promising results. However, the PI3k-based markers (based on current knowledge) surprisingly failed to predict IPAT response. We discovered that MAPK4 activation provides an alternative pathway for AKT activation that is completely independent of the PI3K pathway. Currently, there is no MAPK4-specific inhibitor (although we have started to screen for one). However, our preliminary results suggest that MAPK4 activation of AKT is essential for growth of MAPK4-high TNBC cancer cells. MAPK4 is highly expressed in 30% or more of TNBC. Therefore we will test whether targeting AKT will be effective in the MAPK4-high TNBC, and whether MAPK4 expression defines a large subset of TNBC responsive to AKT blockade. Specifically, using genetic and pharmacological approaches, we will define the role of AKT in mediating MAPK4 tumor-promoting activity in TNBC. Patient Derived Xenograft (PDX) models closely recapitulate human cancers. We will examine whether MAPK4-high TNBC PDXs are more sensitive to AKT inhibitor and whether IPAT represses MAPK4-high TNBC growth. If successful, this study will support the effectiveness of AKT inhibitors in the MAPK4-high subset of TNBC, and thereby identify MAPK4 as a novel molecular marker to stratify TNBC patients for AKT blockade therapy. Particularly because the previous markers failed to predict response in the recent clinical trial, this anticipated outcome would have an immediate and significant impact on TNBC treatment and patient care. The Yang laboratory discovered the alternate MAPK4 pathway for AKT activation. Based on this new paradigm, we are pioneering research on MAPK4 biology in human cancers, including TNBC. If successful, our first-in-field studies will have direct impact on understanding and treatment of TNBC.

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