The present study demonstrated that simultaneously inhibiting HER2/PI3K/AKT/mTOR signaling which also subsequently suppressed endogenous FA lipogenesis and additional exogenous FAs uptake using a combination therapy of PI3K and CD36 inhibitors could significantly reduce the proliferation of anti-HER2 resistant breast cancer cells with PTEN-loss. The gene discussed is PIK3CA; the disease is breast cancer.