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.