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 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 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 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.

• Authors: Chien-Hsing Lu, Shannon L Wyszomierski, Ling-Ming Tseng, Meng-Hong Sun, Keng-Hsueh Lan, Christopher L Neal, Gordon B Mills, Gabriel N Hortobagyi, Francisco J Esteva, Dihua Yu
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 13 Issue 19 Pg. 5883-8 (Oct 01 2007) ISSN: 1078-0432 [Print] United States
• PMID: 17908983 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Antibodies, Monoclonal
• Antibodies, Monoclonal, Humanized
• Ribonucleosides
• triciribine
• Everolimus
• PTEN Phosphohydrolase
• PTEN protein, human
• Bromodeoxyuridine
• Trastuzumab
• Sirolimus

Topics

• Animals
• Antibodies, Monoclonal (pharmacology)
• Antibodies, Monoclonal, Humanized
• Antineoplastic Combined Chemotherapy Protocols (therapeutic use)
• Bromodeoxyuridine (pharmacology)
• Cell Line, Tumor
• Drug Resistance, Neoplasm
• Drug Screening Assays, Antitumor (methods)
• Everolimus
• Female
• Humans
• Mice
• Mice, SCID
• Neoplasm Transplantation
• Neoplasms (drug therapy)
• PTEN Phosphohydrolase (deficiency, genetics)
• Ribonucleosides (administration & dosage)
• Sirolimus (administration & dosage, analogs & derivatives)
• Trastuzumab