Journal
CLINICAL CANCER RESEARCH
Volume 20, Issue 13, Pages 3507-3520Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1078-0432.CCR-13-2769
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Funding
- Department of Defense Innovator Award
- Integrated Program in Translational Research in Human Breast Cancer Research [W81-XWH-05-10395]
- Stand Up To Cancer Dream Team Translational Research Grant, a program of the Entertainment Industry Foundation [SU2C-AACR-DT0409]
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Purpose: Altered PI3K/mTOR signaling is implicated in the pathogenesis of a number of breast cancers, including those resistant to hormonal and HER2-targeted therapies. Experimental Design: The activity of four classes of PI3K/mTOR inhibitory molecules, including a pan-PI3K inhibitor NVP-BKM120), a p110 alpha isoform-specific PI3K inhibitor NVP-BYL719), an mTORC1-specific inhibitor NVP-RAD001), and a dual PI3K/mTORC1/2 inhibitor NVP-BEZ235), was evaluated both in vitro and in vivo against a panel of 48 human breast cell lines. Results: Each agent showed significant antiproliferative activity in vitro, particularly in luminal estrogen receptor-positive and/or HER2(+) cell lines harboring PI3K mutations. In addition, monotherapy with each of the four inhibitors led to significant inhibition of in vivo growth in HER2(+) breast cancer models. The PI3K/mTOR pathway inhibitors were also effective in overcoming both de novo and acquired trastuzumab resistance in vitro and in vivo. Furthermore, combined targeting of HER2 and PI3K/mTOR leads to increased apoptosis in vitro and induction of tumor regression in trastuzumab-resistant xenograft models. Finally, as previously shown, targeting mTORC1 alone with RAD001 leads to consistent feedback activation of AKT both in vitro and in vivo, whereas the dual mTOR1-2/PI3K inhibitor BEZ235 eliminates this feedback loop. However, despite these important signaling differences, both molecules are equally effective in inhibiting tumor cell proliferation both in vitro and in vivo. Conclusion: These preclinical data support the findings of the BOLERO 3 trial that shows that targeting of the PI3K/mTOR pathway in combination with trastuzumab is beneficial in trastuzumab-resistant breast cancer. (C)2014 AACR.
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