Suppression of HER2/HER3-mediated growth of breast cancer cells with combinations of GDC-0941 PI3K inhibitor, trastuzumab, and pertuzumab
Clinical Cancer Research, ISSN: 1078-0432, Vol: 15, Issue: 12, Page: 4147-4156
2009
- 123Citations
- 104Captures
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Example: if you select the 1-year option for an article published in 2019 and a metric category shows 90%, that means that the article or review is performing better than 90% of the other articles/reviews published in that journal in 2019. If you select the 3-year option for the same article published in 2019 and the metric category shows 90%, that means that the article or review is performing better than 90% of the other articles/reviews published in that journal in 2019, 2018 and 2017.
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Metrics Details
- Citations123
- Citation Indexes118
- 118
- CrossRef96
- Patent Family Citations5
- 5
- Captures104
- Readers104
- 104
Article Description
Purpose: Oncogenic activation of the phosphatidylinositol 3-kinase (PI3K) signaling pathway is prevalent in breast cancer and has been associatedwith resistance to HER2 inhibitors in the clinic. We therefore investigated the combinatorial activity of GDC-0941, a novel class I PI3K inhibitor, with standard-of-care therapies for HER2-amplified breast cancer. Experimental Design: Three-dimensional laminin-rich extracellular matrix cultures of human breast cancer cells were utilized to provide a physiologically relevant approach to analyze the efficacy and molecular mechanism of combination therapies ex vivo. Combination studies were done using GDC-0941 with trastuzumab (Herceptin), pertuzumab, lapatinib (Tykerb), and docetaxel, the principal therapeutic agents that are either approved or being evaluated for treatment of early HER2-positive breast cancer. Results: Significant GDC-0941 activity (EC <1 μmol/L) was observed for >70% of breast cancer cell lines that were examined in three-dimensional laminin-rich extracellular matrix culture. Differential responsiveness to GDC-0941 as a single agent was observed for luminal breast cancer cells upon stimulation with the HER3 ligand, heregulin. Combined treatment of GDC-0941, trastuzumab, and pertuzumab resulted in growth inhibition, altered acinar morphology, and suppression of AKT mitogen-activated protein kinase (MAPK) / extracellular signed-regulated kinase (ERK) kinase and MEK effector signaling pathways for HER2-amplified cells in both normal and heregulin-supplemented media. The GDC-0941 and lapatinib combination further showed that inhibition of HER2 activity was essential for maximum combinatorial efficacy. PI3K inhibition also rendered HER2-amplified BT-474M1 cells and tumor xenografts more sensitive to docetaxel. Conclusions: GDC-0941 is efficacious in preclinical models of breast cancer. The addition of GDC-0941 to HER2-directed treatment could augment clinical benefit in breast cancer patients. ©2009 American Association for Cancer Research.
Bibliographic Details
http://www.scopus.com/inward/record.url?partnerID=HzOxMe3b&scp=67449168372&origin=inward; http://dx.doi.org/10.1158/1078-0432.ccr-08-2814; http://www.ncbi.nlm.nih.gov/pubmed/19509167; http://clincancerres.aacrjournals.org/cgi/doi/10.1158/1078-0432.CCR-08-2814; https://syndication.highwire.org/content/doi/10.1158/1078-0432.CCR-08-2814; https://aacrjournals.org/clincancerres/article/15/12/4147/73750/Suppression-of-HER2-HER3-Mediated-Growth-of-Breast; https://dx.doi.org/10.1158/1078-0432.ccr-08-2814; https://clincancerres.aacrjournals.org/content/15/12/4147
American Association for Cancer Research (AACR)
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