Acquired drug resistance represents a major obstacle to using sunitinib for the treatment of solid tumors. Here, we examined cellular and molecular alterations in tumors that are associated with acquired brain tumor resistance to sunitinib using an in vivo model. U87MG tumors obtained from nude mice that received sunitinib 40 mg/kg/day for 30 days were classified as sunitinib-sensitive and -resistant groups based on tumor volume and underwent targeted gene microarray and protein array analyses. The expression of several angiogenesis-associated genes was significantly modulated in sunitinib-treated tumors compared with those in control tumors (p < 0.05), whereas no significant differences were observed between sunitinib-sensitive and -resistant tumors (p > 0.05). Tumor vasculature based on microvessel density, neurogenin 2 chondroitin sulfate proteoglycan (NG2) density and α-smooth muscle actin (α-SMA) density was also similar in sunitinib-treatment groups (p > 0.05). The moderate increase in unbound sunitinib tumor-to-plasma area-under-the-curve (AUC) ratio in sunitinib-resistant mice was accompanied by upregulated ABCG2 expression in tumor. The most profound difference between sunitinib-sensitive and -resistant groups was found in the expression of several phosphorylated proteins involved in intracellular signaling. In particular, phospholipase C-γ1 (PLC-γ1) phosphorylation in sunitinib-resistant tumors was upregulated by 2.6 folds compared with that in sunitinib-sensitive tumors (p < 0.05). In conclusion, acquired sunitinib resistance in U87MG tumors is not associated with revascularization in tumors, but rather with activation of alternate pro-survival pathways involved in an escape mechanism facilitating tumor growth and possibly insufficient drug uptake in tumor cells due to an upregulated membrane efflux transporter.
- Received May 2, 2012.
- Revision received August 2, 2012.
- Accepted August 3, 2012.
- The American Society for Pharmacology and Experimental Therapeutics