Abstract 405: Caveolin-1 expression mediates response to albumin-bound paclitaxel

Abstract

Abstract BACKGROUND: Albumin-bound chemotherapies such as nab-paclitaxel are approved to treat pancreatic cancer, non-small cell lung cancer (NSCLC), and breast cancer. Predictive biomarkers to select patients who may benefit most from nab-paclitaxel are lacking. Nab-paclitaxel is thought to enter cells through a caveolae-gp60 endocytic mechanism. Caveolin-1 (Cav-1) is a principal structural component of caveolae, and Cav-1 has been shown to be important for albumin uptake in endothelial cells. Cav-1 is known to be up-regulated in multiple tumor types, including pancreatic cancer, and certain subtypes of non-small cell lung cancer, and breast cancer. We hypothesize that Cav-1 expression may predict response to nab-paclitaxel therapy. METHODS: We correlated Cav-1 expression with nab-paclitaxel sensitivity in a panel of NSCLC and pancreatic cancer cell lines. We also assessed albumin uptake in tumor and non-tumor cell lines. We genetically depleted Cav-1 by shRNA in cells and performed cytotoxicity assays. In addition, we measured how Cav-1 levels affected albumin and nab-paclitaxel uptake into tumor cells by immunofluorescence, immunoblotting, and mass spectrometry. Annexin V flow cytometry analysis and immunoblotting for apoptosis pathway intermediates were also performed. Nab-paclitaxel resistant cell lines were created by culturing cells with increasing doses of nab-paclitaxel for extended periods of time. The role of Cav-1 expression in mediating response to nab-paclitaxel in vivo was assessed using xenograft models. RESULTS: H23 and MIA-PaCa2 tumor cells uptake more albumin compared to FHs74Int and HBEC3KT non-tumor cell lines. Higher Cav-1 expression in a panel of pancreatic cancer and NSCLC cell lines was correlated with lower IC50 for nab-paclitaxel. Cav-1 depletion resulted in reduced albumin and nab-paclitaxel uptake by tumor cells as measured by immunofluorescence, immunoblotting, and mass spectrometry. Loss of Cav-1 resulted in resistance to nab-paclitaxel but no change in sensitivity to free paclitaxel in vitro. Cav-1 down-regulation resulted in protection from nab-paclitaxel-induced apoptosis. Conversely, re-expression of Cav-1 in low-Cav-1 endogenously expressing cell lines AsPC-1 and HPAFII resulted in increased nab-paclitaxel uptake and sensitization through apoptosis. Furthermore, nab-paclitaxel resistant cells generated by prolonged exposure demonstrated downregulation of Cav-1 levels and reduced albumin uptake. Finally, genetic depletion of Cav-1 rendered tumor cells resistant to nab-paclitaxel in xenograft models, with concomitant reduced albumin uptake and activation of apoptosis. CONCLUSIONS: Our data suggest that Cav-1 expression and caveolae are critical determinants of response to nab-paclitaxel. This data supports further testing of Cav-1 as a potential predictive biomarker of response to nab-paclitaxel and potentially other albumin-bound chemotherapies. Citation Format: Terence M. Williams, Moumita Chatterjee, Ryan Robb, Marally Vedaie, Star Seum, Thirumoorthy Krishnan, Palanichamy Kamalakanan, Edgar Ben-Josef, Arnab Chakravarti. Caveolin-1 expression mediates response to albumin-bound paclitaxel. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 405.