PT - JOURNAL ARTICLE AU - Qingyu Zhou AU - Hua Lv AU - Amin R. Mazloom AU - Huilei Xu AU - Avi Ma'ayan AU - James M. Gallo TI - Activation of Alternate Prosurvival Pathways Accounts for Acquired Sunitinib Resistance in U87MG Glioma Xenografts AID - 10.1124/jpet.112.196097 DP - 2012 Nov 01 TA - Journal of Pharmacology and Experimental Therapeutics PG - 509--519 VI - 343 IP - 2 4099 - http://jpet.aspetjournals.org/content/343/2/509.short 4100 - http://jpet.aspetjournals.org/content/343/2/509.full SO - J Pharmacol Exp Ther2012 Nov 01; 343 AB - Acquired drug resistance represents a major obstacle to using sunitinib for the treatment of solid tumors. Here, we examined the cellular and molecular alterations in tumors that are associated with acquired brain tumor resistance to sunitinib by using an in vivo model. U87MG tumors obtained from nude mice that received sunitinib (40 mg/kg/day) for 30 days were classified into 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 density, and α-smooth muscle actin density was also similar in sunitinib-treatment groups (p > 0.05). The moderate increase in unbound sunitinib tumor-to-plasma area-under-the-curve ratio in sunitinib-resistant mice was accompanied by up-regulated ATP-binding cassette G2 expression in tumor. The most profound difference between the sunitinib-sensitive and -resistant groups was found in the expression of several phosphorylated proteins involved in intracellular signaling. In particular, phospholipase C-γ1 phosphorylation in sunitinib-resistant tumors was up-regulated by 2.6-fold 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 the activation of alternate prosurvival pathways involved in an escape mechanism facilitating tumor growth and possibly insufficient drug uptake in tumor cells caused by an up-regulated membrane efflux transporter.