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

By Yoichi Nagata, K. Lan, Xiaoyan Zhou, Ming Tan, F. Esteva, A. Sahin, Kristine S. Klos, Ping Li, B. Monia, Nina T. Nguyen and 3 more. Cancer Cell, 2004

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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.

Subfields: Molecular Biology, Oncology, Radiology, Nuclear Medicine and Imaging

View Paper: https://www.semanticscholar.org/paper/22998849920ad7128838a1a06bef18198184b756

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Citations in the corpus

Insulin-like growth factor-I receptor/human epidermal growth factor receptor 2 heterodimerization contributes to trastuzumab resistance of breast cancer cells. (2005, background): “Another very important and interesting potential mechanism of trastuzumab resistance, described by Nagata et al. ( 21 ), is decreased expression of the phosphatase and tensin homologue (PTEN).”
Ligand-independent HER2/HER3/PI3K complex is disrupted by trastuzumab and is effectively inhibited by the PI3K inhibitor GDC-0941. (2009, background): “Furthermore, trastuzumab is reported to have either no effect on HER2 activation status or to cause a rapid increase or decrease of HER2 phosphorylation (Lane et al., 2000; Nagata et al., 2004; Sarup et al., 1991).”
EMT, cancer stem cells and drug resistance: an emerging axis of evil in the war on cancer (2010, background): “A direct relationship has been shown in breast cancers that exhibit PTEN loss, as these tumors are resistant to the HER2/Erb2-targeting antibody trastuzumab (Herceptin; Nagata et al., 2004).”
Tumor infiltrating lymphocytes are prognostic in triple negative breast cancer and predictive for trastuzumab benefit in early breast cancer: results from the FinHER trial. (2014, background): “Additional aberrations in the PI3K/AKT, ERK1/2, SRC signaling pathways and loss of PTEN are thought to contribute to resistance but are yet to be validated in the clinical setting [12–14].”
Lipid signalling in disease (2008, methodology): “Collective data indicate that they will be of value in combination therapy: PI3K inhibitors have been shown to reverse resistance to trastuzumab (herceptin, a monoclonal antibody directed against ERBB2), which was caused by the loss of PTE”
Trastuzumab: mechanism of action, resistance and future perspectives in HER2-overexpressing breast cancer. (2007, background): “[33], who demonstrated that trastuzumab specifically inhibits PI3K signalling by reducing PTEN tyrosine phosphorylation and by increasing PTEN membrane localisation and phosphatase activity.”
Targeting PI3K signalling in cancer: opportunities, challenges and limitations (2009, background): “Although loss of PTEN might not absolutely preclude the capacity for RTK inhibitors to shut off PI3K signalling, it seems to reduce the likelihood of cancers responding to these therapies as single agent”
PIK3CA mutations correlate with hormone receptors, node metastasis, and ERBB2, and are mutually exclusive with PTEN loss in human breast carcinoma. (2005, background): “This is clinically significant as intact PTEN is required for therapeutic response to Herceptin (21).”