Abstract 1374: Cross-resistance and sensitivity of sunitinib resistant tumor cells

Abstract

Abstract Background: Resistance to sunitinib, a multi-targeted anti-angiogenic tyrosine kinase inhibitor (TKI) approved for clinical use in advanced renal cell cancer, gastrointestinal stromal tumors and pancreatic neuroendocrine tumors, represents a major clinical problem. Previously we have shown that tumor cells acquire resistance in vitro by continuous incubation with sunitinib and found that acidic lysosomal sequestration of sunitinib mediates its resistance. In this study, we investigated whether sunitinib resistant tumor cells are cross-resistant to other clinically relevant inhibitors and whether agents interfering with lysosomal function can modulate resistance. Methods: Continuous exposure to sunitinib for more than 12 months resulted in drug resistance in 786-O (RCC) and HT-29 (colorectal cancer) cell lines. Using these cells, cross-resistance to other clinically available TKIs such as sorafenib, pazopanib and erlotinib, and to the mTOR inhibitor everolimus, was determined in proliferation assays (MTT). In addition, modulation of sunitinib resistance by the lysosomal inhibitors (LIs) chloroquine and bafilomycin A1 was studied using proliferation assays. The effect of LIs on phosphorylation of key signaling proteins was determined by western blotting. Results: Compared to parental cell lines, proliferation assays revealed that sunitinib resistant cell lines were cross-resistant to pazopanib and erlotinib, while no significant decrease in sensitivity to sorafenib or everolimus was observed. Both chloroquine and bafilomycin A1 were able to modulate sunitinib resistance. Western blot analysis revealed that phosphorylation of key signaling proteins including Akt and p44/42-MAPK was inhibited in sunitinib resistant cells upon co-incubation with chloroquine, while sunitinib alone did not inhibit phosphorylation of these kinases. Conclusion: We found that sunitinib resistant tumor cells are cross-resistant to pazopanib and erlotinib, but remain sensitive to sorafenib and everolimus. Furthermore, combination with the lysosomal inhibitor chloroquine resulted in inhibition of key signaling proteins in sunitinib resistant cells. Taken together, we envision that these findings are relevant for clinical treatment strategies in patients with renal cell cancer resistant to sunitinib. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1374. doi:1538-7445.AM2012-1374