HER2 overexpression drives Akt signaling and cell survival and HER2-enriched
breast tumors have a poor outcome when Akt is upregulated. Akt is activated by phosphorylation at T308 via PI3K and S473 via
mTORC2. The importance of PI3K-activated Akt signaling is well documented in HER2-amplified
breast cancer models, but the significance of mTORC2-activated Akt signaling in this setting remains uncertain. We report here that the
mTORC2 obligate cofactor Rictor is enriched in HER2-amplified samples, correlating with increased phosphorylation at S473 on Akt. In invasive
breast cancer specimens, Rictor expression was upregulated significantly compared with nonmalignant tissues. In a HER2/Neu mouse model of
breast cancer, genetic ablation of Rictor decreased cell survival and phosphorylation at S473 on Akt, delaying
tumor latency, penetrance, and burden. In HER2-amplified cells, exposure to an
mTORC1/2 dual
kinase inhibitor decreased Akt-dependent cell survival, including in cells resistant to
lapatinib, where cytotoxicity could be restored. We replicated these findings by silencing Rictor in
breast cancer cell lines, but not silencing the
mTORC1 cofactor Raptor (RPTOR). Taken together, our findings establish that Rictor/
mTORC2 signaling drives Akt-dependent
tumor progression in HER2-amplified breast
cancers, rationalizing clinical investigation of dual
mTORC1/2
kinase inhibitors and developing mTORC2-specific inhibitors for use in this setting.
Cancer Res; 76(16); 4752-64. ©2016 AACR.