Candidate genes for sensitivity and resistance of human glioblastoma multiforme cell lines to erlotinib

Abstract

Object The authors have previously reported that erlotinib, an EGFR tyrosine kinase inhibitor, exerts widely variable antiproliferative effects on 9 human glioblastoma multiforme (GBM) cell lines in vitro and in vivo. These effects were independent of EGFR baseline expression levels, raising the possibility that more complex genetic properties form the molecular basis of the erlotinib-sensitive and erlotinib-resistant GBM phenotypes. The aim of the present study was to determine candidate genes for mediating the cellular response of human GBMs to erlotinib. Methods Complementary RNA obtained in cell lines selected to represent the sensitive, somewhat responsive, and resistant phenotypes were hybridized to CodeLink Human Whole Genome Bioarrays. Results Expression analysis of 814 prospectively selected genes involved in major proliferation and apoptosis signaling pathways identified 19 genes whose expression significantly correlated with phenotype. Functional annotation analysis revealed that 2 genes (DUSP4 and STAT1) were significantly associated with sensitivity to erlotinib, and 10 genes (CACNG4, FGFR4, HSPA1B, HSPB1, NFATC1, NTRK1, RAC1, SMO, TCF7L1, and TGFB3) were associated with resistance to erlotinib. Moreover, 5 genes (BDNF, CARD6, FOSL1, HSPA9B, and MYC) involved in antiapoptotic pathways were unexpectedly found to be associated with sensitivity. Gene expressions were confirmed by quantitative polymerase chain reaction. Conclusions Based on an analysis of gene expressions in cell lines with sensitive, somewhat responsive, and resistant phenotypes, the authors propose candidate genes for GBM response to erlotinib. The 10 gene candidates for conferring GBM resistance to erlotinib may represent therapeutic targets for enhancing the efficacy of erlotinib against GBMs. Five additional genes warrant further investigation into their role as putative cotargets of erlotinib.

MKNK1 is a YB-1 target gene responsible for imparting trastuzumab resistance and can be blocked by RSK inhibition

“…For example, inhibition of inhibitor of apoptosis-family members cIAP1 (BIRC2) and cIAP2 (BIRC3) increases apoptosis in response to trastuzumab, lapatinib or gefitinib in HER2-overexpressing cells (Foster et al, 2009), whereas inhibition of MCL-1 sensitizes cells to both lapatinib and trastuzumab (Henson et al, 2006;Martin et al, 2008). Moreover, TNFSF18 and TCF7L1 are associated with tamoxifen and erlotinib resistance, respectively (Treeck et al, 2004;Halatsch et al, 2009). Therefore, upregulation of these anti-apoptotic factors by YB-1 likely has a role in promoting resistance to trastuzumab.…”

Combined Inhibition of HER1/EGFR and RAC1 Results in a Synergistic Antiproliferative Effect on Established and Primary Cultured Human Glioblastoma Cells

“…However, despite a solid theoretical background, translation of HER1/EGFR inhibition into clinical practice failed altogether in the setting of glioblastoma (11,12). Because the responsiveness of glioblastoma cells toward erlotinib shows a high variability (13,35), we previously hypothesized that gene expression analysis of glioblastoma cells with an erlotinib-responsive or -resistant phenotype might unveil potential molecular targets allowing the design of a multitargeted approach to suffocate escape mechanisms or cross-talk between oncogenic pathways, ultimately conveying a therapeutic benefit to patients with glioblastoma (13). In this study, combined treatment with erlotinib and inhibitors of those previously identified candidate genes for resistance toward erlotinib revealed that NSC23766, an inhibitor of RAC1, represents the most promising partner for enhancing the antineoplastic effects exerted by erlotinib.…”

“…We previously identified several genes that were overexpressed in erlotinib-resistant glioblastoma cell lines, whereas a decreased expression of these genes was shown in erlotinib-sensitive glioblastoma cells (13). To determine whether inhibition of the products of these candidate resistance genes enhances the antiproliferative effect of erlotinib on established glioblastoma cell lines, we conducted MTT assays for screening purposes.…”

“…To partially reconcile the paradox that inhibition of HER1/EGFR, a proto-oncogene dysregulated so frequently in glioblastoma, has failed in the clinical setting, we previously identified a panel of candidate genes for resistance toward erlotinib (13). These genes were shown to share the common features of increased expression in erlotinib-resistant glioblastoma cell lines and decreased expression in erlotinib-sensitive glioblastoma cell lines.…”

Targeted Therapy for Gliomas: the Oncolytic Virus Applications

“…Rac1 plays a role as a pleiotropic regulator of multiple cellular functions including actin skeleton reorganization, gene transcription and cell migration. Rac1 is a key contributor to glioma cell survival, probably via multiple signaling pathways including JNK (Halatsch et al, 2009) but is found to be critical for the replication of oncolytic NDV to the highly tumorigenic ras-transformed skin carcinoma cells However, despite several entry-line association, there are several physicals barriers that is present in the gliomas microenvironment that blocks the virus distribution. The extracellular matrix (ECM), hypoxic region, and high interstitial pressure are amongst the major challenge in achieving lasting oncolytic virus infection (Franz et al, 2010) Besides that, GBM is currently described with multiple interactive dysregulated cell signalings pathway and this could lead to the inconsistency of outcome (Chamberline et al, 2006) in bigger population target.…”