Activation of EGFR signaling pathway leads to prostate cancer bone metastasis; however, therapies targeting EGFR have demonstrated limited effectiveness and led to drug resistance. miR-203 levels are down-regulated in clinical samples of primary prostate cancer and further reduced in metastatic prostate cancer. Here we show that ectopic miR-203 expression displayed reduced bone metastasis and induced sensitivity to tyrosine kinase inhibitors (TKIs) treatment in a xenograft model. Our results demonstrate that the induction of bone metastasis and TKI resistance require miR-203 down-regulation, activation of the EGFR pathway via altered expression of EGFR ligands (EREG and TGFA) and anti-apoptotic proteins (API5, BIRC2, and TRIAP1). Importantly, a sufficient reconstitution of invasiveness and resistance to TKIs treatment was observed in cells transfected with anti-miR-203. In prostate cancer patients, our data showed that miR-203 levels were inversely correlated with the expression of two EGFR ligands, EREG and TGFA, and an EGFR dependent gene signature. Our results support the existence of a miR-203, EGFR, TKIs resistance regulatory network in prostate cancer progression. We propose that the loss of miR-203 is a molecular link in the progression of prostate cancer metastasis and TKIs resistance characterized by high EGFR ligands output and anti-apoptotic proteins activation.
The R521K polymorphism of epidermal growth factor receptor has attenuated affinity in ligand binding and proto-oncogene induction, which may affect the efficacy of cetuximab. We analyzed the effect of this polymorphism on the outcome of 112 patients with KRAS wild-type metastatic colorectal carcinoma treated with first-line cetuximab plus FOLFOX-4. The associations of this polymorphism with vascular endothelial growth factor (VEGF) expression and clinicopathologic characteristics were also examined. The results showed that the frequencies of the G/G, G/A, and A/A genotypes were 32.1% (n = 36), 42.9% (n = 48), and 25.0% (n = 28), respectively. A marked decrease in VEGF expression levels (66.7% vs 28.9%, P < 0.01) was observed in patients with 521A allele variants (Arg/Lys or Lys/Lys), which were associated with a decreased tumor size (55.6% vs 31.6%, P = 0.02), good histological differentiation (63.9% vs 85.5%, P = 0.01), decreased lymphovascular invasion (69.4% vs 39.5%, P < 0.01), and a higher response rate to cetuximab plus FOLFOX treatment (55.6% vs 78.9%, P = 0.01). In addition, this polymorphism was associated with a longer progression-free period (P = 0.001) and overall survival (P = 0.001). By multivariate analysis, this polymorphism was also identified as an independent prognostic factor. These data suggest that the R521K polymorphism of epidermal growth factor receptor, by reducing its activation and a consequential downregulation of its target genes, including VEGF, could be a key determinant of an increased response to cetuximab-based chemotherapy and a longer survival for KRAS wild-type colorectal carcinoma patients. (Cancer Sci 2012; 103: 791-796) C etuximab, a chimeric mAb, is an antibody against the extracellular domain of epidermal growth factor receptor (EGFR).(1) It binds to EGFR with a high affinity and is able to compete with epidermal growth factor (EGF) binding, thereby inhibiting subsequent receptor activation and signalling.( 1) Cetuximab is approved for the treatment of patients with metastatic colorectal carcinoma (CRC) and squamous carcinoma of the head and neck. A favorable effect of cetuximab combined with chemotherapy in advanced non-small-cell lung cancer (NSCLC) has also been reported.(2) The benefits of cetuximabbased therapies are restricted to a particular subgroup of patients. The EGFR expression, as evaluated by immunohistochemistry, does not correlate with the response to cetuximab, (3) but an increase in EGFR copy number identified by FISH, may predict a better response.(4) Loss of phosphatase and tensin homolog (PTEN) protein expression is also associated with a lower response rate. Mutations of KRAS, a gene encoding a G protein that plays a key role in the downstream signaling of EGFR, lead to resistance to cetuximab.(6) Mutations of KRAS occur in approximately 40% of CRC, and the mutation status of KRAS is considered a good predictive marker for cetuximab-based treatment.(6) Mutations of the v-raf murine sarcoma viral oncogene homolog B1 (BRAF) and PIK3CA genes are al...
PTEN deletion was associated with poor survival.
Drug repurposing aims to find novel indications of clinically used or experimental drugs. Because drug data already exist, drug repurposing may save time and cost, and bypass safety concerns. Polypharmacology, one drug with multiple targets, serves as a basis for drug repurposing. Large-scale databases have been accumulated in recent years, and utilization and integration of these databases would be highly helpful for polypharmacology and drug repurposing. The Connectivity Map (CMap) is a database collecting gene-expression profiles of drug-treated human cancer cells, which has been widely used for investigation of polypharmacology and drug repurposing. In this study, we integrated the next-generation L1000-based CMap and an analytic Web tool, the L1000FWD, for systematic analyses of polypharmacology and drug repurposing. Two different types of anti-cancer drugs were used as proof-of-concept examples, including histone deacetylase (HDAC) inhibitors and topoisomerase inhibitors. We identified KM-00927 and BRD-K75081836 as novel HDAC inhibitors and mitomycin C as a topoisomerase IIB inhibitor. Our study provides a prime example of utilization and integration of the freely available public resources for systematic polypharmacology analysis and drug repurposing.
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