Rictor/mTORC2 Drives Progression and Therapeutic Resistance of HER2-Amplified Breast Cancers.

Morrison Joly M, Hicks DJ, Jones B, Sanchez V, Estrada MV, Young C, Williams M, Rexer BN, Sarbassov dos D, Muller WJ, Brantley-Sieders D, Cook RS
Cancer Res. 2016 76 (16): 4752-64

PMID: 27197158 · PMCID: PMC5758362 · DOI:10.1158/0008-5472.CAN-15-3393

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.

©2016 American Association for Cancer Research.

MeSH Terms (20)

Animals Blotting, Western Breast Neoplasms Carrier Proteins Disease Progression Drug Resistance, Neoplasm Female Heterografts Humans Kaplan-Meier Estimate Mechanistic Target of Rapamycin Complex 2 Mice Mice, Inbred BALB C Mice, Nude Multiprotein Complexes Rapamycin-Insensitive Companion of mTOR Protein Receptor, ErbB-2 Signal Transduction Tissue Array Analysis TOR Serine-Threonine Kinases

Connections (1)

This publication is referenced by other Labnodes entities:

Links