Therapeutic sensitivity to Rac GTPase inhibition requires consequential suppression of mTORC1, AKT, and MEK signaling in breast cancer

• Published in: Oncotarget Vol. 8; no. 13; pp. 21806 - 21817
• Main Authors: Hampsch, Riley A, Shee, Kevin, Bates, Darcy, Lewis, Lionel D, Désiré, Laurent, Leblond, Bertrand, Demidenko, Eugene, Stefan, Kurtis, Huang, Yina H, Miller, Todd W
• Format: Journal Article
• Language: English
• Published: United States Impact Journals LLC 28.03.2017
• Subjects: Animals; Antineoplastic Agents - pharmacology; Breast Neoplasms - metabolism; Drug Resistance, Neoplasm - physiology; Female; Humans; MAP Kinase Kinase Kinases - metabolism; Mechanistic Target of Rapamycin Complex 1; Mice; Mice, Inbred NOD; Mice, SCID; Multiprotein Complexes - metabolism; Protein Kinase Inhibitors - pharmacology; Proto-Oncogene Proteins c-akt - antagonists & inhibitors; Proto-Oncogene Proteins c-akt - metabolism; Research Paper; Signal Transduction - drug effects; TOR Serine-Threonine Kinases - metabolism; Xenograft Model Antitumor Assays; mTOR; Rac3; breast cancer; Rac1; ERK
• ISSN: 1949-2553; 1949-2553
• DOI: 10.18632/oncotarget.15586

Rac GTPases have oncogenic roles in cell growth, survival, and migration. We tested response to the Rac inhibitor EHT1864 in a panel of breast cancer cell lines. EHT1864-induced growth inhibition was associated with dual inhibition of the PI3K/AKT/mTORC1 and MEK/ERK pathways. Breast cancer cells harboring PIK3CA mutations or HER2 overexpression were most sensitive to Rac inhibition, suggesting that such oncogenic alterations link Rac activation with PI3K/AKT/mTORC1 and MEK/ERK signaling. Interestingly, EHT1864 decreased activation of the mTORC1 substrate p70S6K earlier than AKT inhibition, suggesting that Rac may activate mTORC1/p70S6K independently of AKT. Comparison of the growth-inhibitory profile of EHT1864 to 137 other anti-cancer drugs across 656 cancer cell lines revealed significant correlation with the p70S6K inhibitor PF-4708671. We confirmed that Rac complexes contain MEK1/2 and ERK1/2, but also contain p70S6K; these interactions were disrupted by EHT1864. Pharmacokinetic profiles revealed that EHT1864 was present in mouse plasma at concentrations effective in vitro for approximately 1 h after intraperitoneal administration. EHT1864 suppressed growth of HER2+ tumors, and enhanced response to anti-estrogen treatment in ER+ tumors. Further therapeutic development of Rac inhibitors for HER2+ and PIK3CA-mutant cancers is warranted.