Journal
CANCER RESEARCH
Volume 77, Issue 21, Pages 5925-5937Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/0008-5472.CAN-17-0604
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Funding
- American Cancer Society [IRG-67-003-47]
- National Center for Advancing Translational Sciences [KL2TR001068]
- Ohio State University Comprehensive Cancer Center (OSU-CCC)
- NIH [R01 CA198128, P30 CA016058]
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Nab-paclitaxel, a nanoparticle conjugate of paclitaxel tohuman albumin, exhibits efficacy in pancreatic cancer, non-small cell lung cancer and breast cancer. However, there is a lack of predictive biomarkers to identify patients who might benefit most from its administration. This study addresses this gap in knowledge by identifying that caveolin-1 (Cav-1) is a candidate mechanismbased biomarker. Caveolae are small membrane invaginations important for transendothelial albumin uptake. Cav-1, the principal structural component of caveolae, is overexpressed in the cancers noted above that respond to nab-paclitaxel. Thus, we hypothesized that Cav-1 may be critical for albumin uptake in tumors and perhaps determine their response to this drug. Cav-1 protein levels correlated positively with nab-paclitaxel sensitivity. RNAi-mediated attenuation of Cav-1 expression reduced uptake of albumin and nab-paclitaxel in cancer cells and rendered them resistant to nab-paclitaxel-induced apoptosis. Conversely, Cav-1 overexpression enhanced sensitivity to nab-paclitaxel. Selection for cellular resistance to nab-paclitaxel in cell culture correlated with a loss of Cav-1 expression. In mouse xenograft models, cancer cells, where Cav-1 was attenuated, exhibited resistance to the antitumor effects of nab-paclitaxel therapy. Overall, our findings suggest Cav-1 as a predictive biomarker for the response to nab-paclitaxel and other albumin-based cancer therapeutic drugs. (C) 2017 AACR.
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