PTEN activation contributes to tumor inhibition by trastuzumab, and loss of PTEN predicts trastuzumab resistance in patients.

The ErbB2-targeting antibody, trastuzumab (Herceptin), has remarkable therapeutic efficacy in certain patients with ErbB2-overexpressing tumors. The overall trastuzumab response rate, however, is limited and what determines trastuzumab response is poorly understood. Here we report that PTEN activation contributes to trastuzumab's antitumor activity. Trastuzumab treatment quickly increased PTEN membrane localization and phosphatase activity by reducing PTEN tyrosine phosphorylation via Src inhibition. Reducing PTEN in breast cancer cells by antisense oligonucleotides conferred trastuzumab resistance in vitro and in vivo. Patients with PTEN-deficient breast cancers had significantly poorer responses to trastuzumab-based therapy than those with normal PTEN. Thus, PTEN deficiency is a powerful predictor for trastuzumab resistance. Additionally, PI3K inhibitors rescued PTEN loss-induced trastuzumab resistance, suggesting that PI3K-targeting therapies could overcome this resistance.

• Publication year

  2004

• Venue

  Cancer Cell

• Publication date

  2004-04-01

• Fields of study

  Medicine

• Identifiers
  DOI 10.1016/J.CCR.2004.06.022PMID 15324695
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• PI3K inhibitors rescue PTEN loss-induced trastuzumab resistance.

  Confidence 0.96

  박진우 (dztg5apj7m) extraction뀨 (7c402c1b98) reviewq (76h6bfydm6) review
• Patients with PTEN-deficient breast cancers have significantly poorer responses to trastuzumab-based therapy than patients with normal PTEN.

  Confidence 0.97

  박진우 (dztg5apj7m) extraction뀨 (7c402c1b98) reviewq (76h6bfydm6) review
• Reducing PTEN with antisense oligonucleotides confers trastuzumab resistance in breast cancer cells in vitro and in vivo.

  Confidence 0.98

  박진우 (dztg5apj7m) extraction뀨 (7c402c1b98) reviewq (76h6bfydm6) review
• Trastuzumab quickly increases PTEN membrane localization and phosphatase activity by reducing PTEN tyrosine phosphorylation through Src inhibition.

  Confidence 0.99

  박진우 (dztg5apj7m) extraction뀨 (7c402c1b98) reviewq (76h6bfydm6) review

• antisense oligonucleotides

  molecular tool, nucleic acid

  Synthetic nucleic acids used here to reduce PTEN expression in breast cancer cells.

  Aliases: ASOs

  박진우 (dztg5apj7m) extraction뀨 (7c402c1b98) reviewq (76h6bfydm6) review
• pi3k inhibitors

  drug class, inhibitor

  Small-molecule inhibitors targeting phosphoinositide 3-kinase signaling in the rescue experiments described here.

  Aliases: phosphoinositide 3-kinase inhibitors

  박진우 (dztg5apj7m) extraction뀨 (7c402c1b98) reviewq (76h6bfydm6) review
• pten

  protein, phosphatase

  A tumor suppressor phosphatase examined for its membrane localization, phosphorylation state, and activity in relation to trastuzumab response.

  박진우 (dztg5apj7m) extraction뀨 (7c402c1b98) reviewq (76h6bfydm6) review
• pten-deficient breast cancers

  cancer subtype, condition

  Breast cancers characterized by low or absent PTEN expression or function in the patient samples discussed here.

  Aliases: PTEN loss breast cancers

  박진우 (dztg5apj7m) extraction뀨 (7c402c1b98) reviewq (76h6bfydm6) review
• src

  kinase, protein

  A tyrosine kinase implicated here in regulating PTEN tyrosine phosphorylation.

  박진우 (dztg5apj7m) extraction뀨 (7c402c1b98) reviewq (76h6bfydm6) review
• trastuzumab

  antibody, therapy

  A monoclonal antibody used here as the ErbB2-targeting therapy evaluated for antitumor effects.

  Aliases: Herceptin

  박진우 (dztg5apj7m) extraction뀨 (7c402c1b98) reviewq (76h6bfydm6) review
• trastuzumab-based therapy

  therapy, treatment regimen

  Treatment regimens that include trastuzumab and were used to assess clinical response in patients.

  박진우 (dztg5apj7m) extraction뀨 (7c402c1b98) reviewq (76h6bfydm6) review
• trastuzumab resistance

  phenotype, treatment response

  The reduced sensitivity to trastuzumab observed in cells and patients in this paper.

  박진우 (dztg5apj7m) extraction뀨 (7c402c1b98) reviewq (76h6bfydm6) review

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