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


METHODS
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.
Lu
Chien-Hsing
CH
Department of Molecular and Cellular Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA.
Wyszomierski
Shannon L
SL
Tseng
Ling-Ming
LM
Sun
Meng-Hong
MH
Lan
Keng-Hsueh
KH
Neal
Christopher L
CL
Mills
Gordon B
GB
Hortobagyi
Gabriel N
GN
Esteva
Francisco J
FJ
Yu
Dihua
D
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D061067:Antibodies, Monoclonal, Humanized; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D001973:Bromodeoxyuridine / Q000494:pharmacology; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor / Q000379:methods*; D000068338:Everolimus; D005260:Female; D006801:Humans; D051379:Mice; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000188:drug therapy*; D051059:PTEN Phosphohydrolase / Q000172:deficiency* / Q000235:genetics*; D012263:Ribonucleosides / Q000008:administration & dosage; D020123:Sirolimus / Q000008:administration & dosage / Q000031:analogs & derivatives; D000068878:Trastuzumab
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D012263:Ribonucleosides; C023764:triciribine; D000068338:Everolimus; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; D001973:Bromodeoxyuridine; D000068878:Trastuzumab; D020123:Sirolimus