Preclinical testing of clinically applicable strategies for overcoming trastuzumab resistance caused by PTEN deficiency

Purpose: We have previously shown that PTEN loss confers trastuzumab resistance in ErbB2overexpressing breast cancer using cell culture, xenograft models, and patient samples. This is a critical clinical problem because trastuzumab is used in a variety of therapeutic regimens, and at the current time, there are no established clinical strategies to overcome trastuzumab resistance. Here, we did preclinical studies on the efficacy of clinically applicable inhibitors of the Akt/mammalian target of rapamycin (mTOR) pathway to restore trastuzumab sensitivity to PTEN-deficient cells. Experimental Design: Cell culture and xenograft models were used to test a panel of clinically applicable, small-molecule inhibitors of the Akt/mTOR signal transcuction pathway, a critical pathway downstream of ErbB2, and identify compounds with the ability to restore trastuzumab sensitivity to PTEN-deficient cells. Results: When trastuzumab was combined with the Akt inhibitor triciribine, breast cancer cell growth was inhibited and apoptosis was induced. In a xenograft model, combination therapy with trastuzumab and triciribine dramatically inhibited tumor growth. The combination of trastuzumab and the mTCR inhibitor RAD001 also slowed breast cancer cell growth in vitro and in vivo. Conclusions: Combining trastuzumab with inhibitors of the Akt/mTOR pathway is a clinically applicable strategy and combinations of trastuzumab with triciribine or RAD001 are promising regimens for rescue of trastuzumab resistance caused by PTEN loss.