Activation of Alternate Prosurvival Pathways Accounts for Acquired Sunitinib Resistance in U87MG Glioma Xenografts

Abstract

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 angiogenesisassociated genes was significantly modulated in sunitinibtreated tumors compared with those in control tumors (p Ͻ 0.05), whereas no significant differences were observed between sunitinib-sensitive and -resistant tumors (p Ͼ 0.05). Tumor vasculature based on microvessel density, neurogenin 2 chondroitin sulfate proteoglycan density, and ␣-smooth muscle actin density was also similar in sunitinib-treatment groups (p Ͼ 0.05). The moderate increase in unbound sunitinib tumor-toplasma 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-␥1 phosphorylation in sunitinib-resistant tumors was up-regulated by 2.6-fold compared with that in sunitinib-sensitive tumors (p Ͻ 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.

Response-Predictive Gene Expression Profiling of Glioma Progenitor Cells In Vitro

“…Yang et al [10] showed that phosphorylated ERK1/2 was not affected, but AKT and STAT3 phosphorylation was substantially reduced in medulloblastoma cell lines after short-term treatment with Sunitinib. Furthermore, in line with the results of Zhou et al [49] , differences of pERK were not statistically relevant to distinguish between Sunitinib sensitive and resistant U87MG glioma xenograft tumors.…”

Induction of multiple drug resistance in HMEC-1 endothelial cells after long-term exposure to sunitinib

“…Probably, as is suggested by a study using an in ex vivo tumor model, prosurvival pathways might also contribute to the acquisition of Su resistance. 20 The elucidation of unknown supplementary mechanisms needs further investigation.…”

A Systems Biology Approach Identifies Effective Tumor–Stroma Common Targets for Oral Squamous Cell Carcinoma

“…This ability of resistance to perturbations is attained through various mechanisms. For example, functional redundancy could enable a tumor to sustain drug attack on a biochemical pathway by finding alternative routes to escape the blockage (39). This redundancy partly contributes to inefficiency of current therapeutic strategies.…”