Preclinical Testing of Clinically Applicable Strategies for Overcoming Trastuzumab Resistance Caused by PTEN Deficiency

Abstract

Purpose: We have previously shown that PTEN loss confers trastuzumab resistance in ErbB2-overexpressing 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 PTENdeficient 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 transduction 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 mTOR inhibitor RAD001also 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.

Whole genome DNA methylation signature of HER2-positive breast cancer

“…7 HER2+ breast cancers are treated with targeted drugs (trastuzumab, lapatinib) along with chemotherapy. Resistance to trastuzumab 8,9 has been found to be due to increased signaling through the PI3K/AKT pathway. Genetic alterations in the PI3K pathway are also implicated in reduced response to lapatinib treatment.…”

ERBB2 juxtamembrane domain (trastuzumab binding site) gene mutation is a rare event in invasive breast cancers overexpressing the ERBB2 gene

“…15,16 Downstream signaling pathway members were proposed as potential source for trastuzumab resistance, including p27 Kip1, PTEN, PI3K, mTOR, and Akt. [17][18][19] Cross-talk with other signaling pathways including insulin-like growth factor receptor-1, ER pathway, and vascular endothelial growth factor that have the ability to bypass ERBB2 blockade have also been proposed to be involved in trastuzumab resistance. [20][21][22] However, these studies were all preclinical or in cell lines, and to date, there are no clinically validated markers to predict de novo or …”

Human epidermal growth factor receptor 2 positive (HER2+) metastatic breast cancer: how the latest results are improving therapeutic options

“…Everolimus is an oral mTOR inhibitor blocking the PI3K pathway. Preclinical studies demonstrated that the combination of everolimus and trastuzumab rescued phosphatase and tensin homolog (PTEN) loss-induced trastuzumab resistance and slowed the growth of HER2+ breast cancer cells [Lu et al 2007]. Everolimus was evaluated as first-line therapy for HER2+ MBC in the BOLERO-1/TRIO 019 trial, that randomized 719 patients with treatment naïve HER2+ MBC in a 2:1 ratio to receive trastuzumab and paclitaxel in combination with everolimus (n = 480) or placebo (n = 239).…”