Abstract 511: Rictor/mTORC2 drives formation, progression and therapeutic resistance of HER2-amplified breast cancers

Proceedings: AACR 106th Annual Meeting 2015; April 18-22, 2015; Philadelphia, PA The phosphatidyl inositol-3-kinase (PI3K)/Akt signaling pathway is aberrantly activated in nearly 60% of breast cancers, through HER2 amplification, PIK3CA mutation, PTEN inactivation, and other alterations. The mTOR complexes mTORC1 and mTORC2 operate as activators (mTORC2) or effectors (mTORC1) of Akt. We found that mRNA upregulation in the mTORC2 cofactors RICTOR and MAPKAP1 correlated with poor survival in breast cancer patients, while upregulation in the mTORC1 cofactor RPTOR did not. Genomic gains of RICTOR and MAPKAP1 occurred more frequently in breast cancers with PI3K pathway alterations than genomic RPTOR gains. Importantly, Rictor protein levels were increased in invasive over non-invasive breast tumors, while Raptor levels were not. RICTOR gene ablation in a transgenic mouse model of HER2-amplified breast cancer delayed tumorigenesis and decreased lung metastasis, Akt-S473 phosphorylation, cell growth and survival. In human HER2-amplified breast cancer cells, Rictor loss, but not Raptor loss, decreased Akt-S473 phosphorylation, reducing cell survival and motility/invasion. Interestingly, Rictor/mTORC2 loss or treatment with a dual mTORC1/2 inhibitor improved lapatinib-induced cell killing in parental and lapatinib-resistant tumor cells to a greater extent than mTORC1 inhibition. Akt re-activation rescued cell survival, but not motility/invasion, in Rictor-depleted cells. However, Rictor loss caused accumulation of the Rac inhibitor RhoGDI2, thus impairing Rac1-dependent invasion. We conclude that HER2-amplified breast cancers use Rictor/mTORC2 to drive Akt-mediated cell survival and Rac1-mediated cellular invasion. These studies support additional studies into mTORC2-specific inhibitors. Citation Format: Meghan M. Morrison, Bayley Jones, Violeta Sanchez, Monica V. Estrada, Donna Hicks, Michelle Williams, Dana Brantley-Sieders, Rebecca Cook. Rictor/mTORC2 drives formation, progression and therapeutic resistance of HER2-amplified breast cancers. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 511. doi:10.1158/1538-7445.AM2015-511