Ligand-independent HER2/HER3/PI3K complex is disrupted by trastuzumab and is effectively inhibited by the PI3K inhibitor GDC-0941.
By T. Junttila, R. Akita, Kathryn L. Parsons, Carter T. Fields, Gail D Lewis Phillips, L. Friedman, D. Sampath, M. Sliwkowski. Cancer Cell, 2009
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Herceptin (trastuzumab) is the backbone of HER2-directed breast cancer therapy and benefits patients in both the adjuvant and metastatic settings. Here, we describe a mechanism of action for trastuzumab whereby antibody treatment disrupts ligand-independent HER2/HER3 interactions in HER2-amplified cells. The kinetics of dissociation parallels HER3 dephosphorylation and uncoupling from PI3K activity, leading to downregulation of proximal and distal AKT signaling, and correlates with the antiproliferative effects of trastuzumab. A selective and potent PI3K inhibitor, GDC-0941, is highly efficacious both in combination with trastuzumab and in the treatment of trastuzumab-resistant cells and tumors.
Subfields: Molecular Biology, Oncology, Radiology, Nuclear Medicine and Imaging
View Paper: https://www.semanticscholar.org/paper/08229001e01a8283e9ab3096c32d014fb4394bad
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Citations in the corpus
- Targeting the cancer kinome through polypharmacology (2010, neutral): “There has been a particular emphasis on the use of PI3K inhibitors to sensitize tumours to inhibitors of EGFR or ERBB2 (such as erlotinib 47 , lapatinib 48 and trastuzumab 49 ).”
- Risk Factors and Preventions of Breast Cancer (2017, background): “Some potential mechanisms may be that trastuzumab can suppress the growth and proliferation of cancer cells by recruiting ubiquitin to internalize and degrade HER2, by activating the immune system against cancer cells via a mechanism called antibody-dependent cell-mediated cytotoxicity (ADCC) or by ”
- Targeting PI3K/Akt signal transduction for cancer therapy (2021, background): “Experiments have shown that monotherapy or combination therapy with GDC0941 and other agents has strong antitumor activity in mouse xenograft models of human cancer.(196,197) BKM120, also known as NVP-BKM120, is another effective panclass I PI3K inhibitor that exerts a strong inhibitory effect on p1”
- DS-8201a, A Novel HER2-Targeting ADC with a Novel DNA Topoisomerase I Inhibitor, Demonstrates a Promising Antitumor Efficacy with Differentiation from T-DM1 (2016, background): “In SK-BR-3 cells, the treatment of trastuzumab decreased about 70% of the Akt phosphorylation (41), suggesting that DXd conjugation may enhance the effect of unconjugated anti-HER2 antibody on pAkt.”
- Strongly enhanced antitumor activity of trastuzumab and pertuzumab combination treatment on HER2-positive human xenograft tumor models. (2009, background): “15), blocking ligand-independent HER2 signaling (16), and inhibiting HER2mediated angiogenesis (17).”
- Pertuzumab plus Trastuzumab plus Docetaxel for Metastatic Breast Cancer (2011, positive): “Trastuzumab binds to subdomain IV of the HER2 extracellular domain and exerts its antitumor effects by blocking HER2 cleavage,(5) stimulating antibody-dependent, cell-mediated cytotoxicity 6 and inhibiting ligand-independent, HER2mediated mitogenic signaling.(7) However, in most patients with HER2-p”
- Treatment of HER2-positive breast cancer: current status and future perspectives (2012, background): “Deregulation of this pathway is thought to be a cause of resistance to HER2-targeted therapies, as well as resistance to cytotoxics and hormonal therapies”