43 research outputs found
SRC and PIM1 as potential co-targets to overcome resistance in MET deregulated non-small cell lung cancer
No full textBackground: The role of MET alterations in non-small cell lung cancer (NSCLC) is increasing and several targeted agents are under evaluation. MET exon 14 skipping mutations and MET amplifications are associated with potential sensitivity to MET inhibition, though resistance mechanisms are emerging. In MET addicted cells, MET inhibition leads to activation of proviral integration site for Moloney murine leukemia virus-1 (PIM1). PIM1 and proto-oncogene tyrosine-protein kinase Src (SRC) can regulate the expression of receptor tyrosine kinases (RTKs), potentially inducing resistance to MET inhibition through cross-activation. Methods: We evaluated the activity of class I-II MET inhibitors, the SRC inhibitor dasatinib, and pan-PIM inhibitors in four MET addicted cell lines. We assessed the effect of the dual MET/PIM and MET/ SRC inhibition on cell viability and at the protein level. We evaluated RNA expression profiles of the cell lines. Advanced NSCLCs were also screened for MET alterations. Results: All cell lines were sensitive to class I-II MET inhibitors. All cell lines were resistant to single PIM and SRC inhibition. Dual MET/PIM inhibition was synergistic or additive in MET amplified cell lines and dual MET/SRC inhibition was highly synergistic in all MET addicted cell lines. The addition of an SRC inhibitor partially prevents the RTKs cross-activation. MET alterations were found in 9 out of 97 evaluable samples (9.3%); median overall survival in MET altered patients was 5 months (95% CI, 3 m-NA). Conclusions: We identified a potential role of PIM inhibition in MET amplified tumors and of SRC inhibition in MET addicted tumors. Potential applications of this new treatment strategy warrant further evaluation
Differential cellular and molecular effects of bortezomib, a proteasome inhibitor, in human breast cancer cells
No full textCo-expression of matrix metalloproteinase-7 (MMP-7) and phosphorylated insulin growth factor receptor I (pIGF-1R) correlates with poor prognosis in patients with wild-type KRAS treated with cetuximab or panitumumab: A GEMCAD study
No full textBackground: By transactivation, phosphorylated insulin growth factor receptor I (IGF-1R) can activate epidermal growth factor receptor (EGFR). MMP-7, produced by colorectal cancer cells, also can activate IGF-1R by degrading IGFBP-3 and releasing IGF-I. Results: Expression of activated IGF-1R and MMP-7 was observed in 51 and 49% of patients, respectively. Coexpression of MMP-7 and pIGF-1R (double positivity, DP) was observed in 28 patients (25%). There was no association between KRAS or BRAF mutational status and DP (p = 0.52). Patients with DP responded more poorly to first-line chemotherapy (p = 0.005) and to anti-EGFR treatment (p = 0.01) than non-DP patients. In wild type (WT) KRAS patients, those with DP have poorer PFS (2.7 vs. 3.5 months, p = 0.036; HR 1.98, 95% CI 1.05-3.75) and OS (6.4 vs. 8.6 months, p = 0.010; HR 2.33, 95% CI 1.23-4.43) in the adjusted multivariate analysis. Methods: A cohort of patients with advanced colorectal cancer (CRC), under second-or third-line treatment with cetuximab or panitumumab, was tested using immunohistochemistry for expression of the activated form of IGF-1R (p-IGF-1R) and MMP-7. KRAS and BRAF mutation status was determined by sequencing and allelic discrimination analysis, respectively. Analyses were performed in primary CRC tumor samples or metastases, and the association of immunohistochemistry findings, mutational results and treatment outcomes was investigated in both univariate and multivariate analyses. Conclusions: Our study suggests that concomitant expression of MMP-7 and activation of p-IGF-1R (DP) correlates with poor prognosis in WT KRAS pts treated with anti-EGFR. © 2011 Landes Bioscience
Update on HER-2 as a target for cancer therapy: alternative strategies for targeting the epidermal growth factor system in cancer
No full textThe epidermal growth factor (EGF) family of ligands and receptors interact to influence cell division, differentiation and motility. Much evidence supports their importance in causing and sustaining cell transformation in model systems and in human cancer. The exact mechanism by which this is achieved varies in different tumour types and from case to case. The EGF system is a target for new types of targeted chemotherapy. The choice of strategy will depend on the mechanism involved, however, and several approaches are under development or evaluation in clinical trials. Each will have a different spectrum of side effects and the potential for development of drug resistance
BIM and mTOR expression levels predict outcome to erlotinib in EGFR-mutant non-small-cell lung cancer
No full textAltres ajuts: Fellowship Award of the International Association for the Study of Lung Cancer i grant of the Italian Association for Cancer Research (AIRC My First AIRC Grant n° 14282).Altres ajuts: RTICC/RD12/0036/0072Abstract.BIM is a proapoptotic protein that initiates apoptosis triggered by EGFR tyrosine kinase inhibitors (TKI). mTOR negatively regulates apoptosis and may influence response to EGFR TKI. We examined mRNA expression of BIM and MTOR in 57 patients with EGFR-mutant NSCLC from the EURTAC trial. Risk of mortality and disease progression was lower in patients with high BIM compared with low/intermediate BIM mRNA levels. Analysis of MTOR further divided patients with high BIM expression into two groups, with those having both high BIM and MTOR experiencing shorter overall and progression-free survival to erlotinib. Validation of our results was performed in an independent cohort of 19 patients with EGFR-mutant NSCLC treated with EGFR TKIs. In EGFR-mutant lung adenocarcinoma cell lines with high BIM expression, concomitant high mTOR expression increased IC50 of gefitinib for cell proliferation. We next sought to analyse the signalling pattern in cell lines with strong activation of mTOR and its substrate P-S6. We showed that mTOR and phosphodiesterase 4D (PDE4D) strongly correlate in resistant EGFR-mutant cancer cell lines. These data suggest that the combination of EGFR TKI with mTOR or PDE4 inhibitors could be adequate therapy for EGFR-mutant NSCLC patients with high pretreatment levels of BIM and mTOR
25P A non-pathway-specific approach in EGFR and KRAS mutant or squamous cell histology non-small cell lung cancer (NSCLC)
No full text24P Proviral integration site for Moloney murine leukemia virus-1 (PIM-1) inhibition with AZD1208 to prevent resistance to osimertinib in EGFR mutant NSCLC
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A combination of LNA probe and EDC cross-linking provides the most sensitive detection of miRNA
No full text<p><b>Copyright information:</b></p><p>Taken from "Carbodiimide-mediated cross-linking of RNA to nylon membranes improves the detection of siRNA, miRNA and piRNA by northern blot"</p><p></p><p>Nucleic Acids Research 2007;35(8):e60-e60.</p><p>Published online 2 Apr 2007</p><p>PMCID:PMC1885651.</p><p>© 2007 The Author(s)</p> Identical 5-μg aliquots of total RNA from HeLa cells were loaded in multiple lanes of the same denaturing polyacrylamide gel. The same volume of P-labelled RNA markers was loaded in each adjacent lane. After electrophoresis and transfer to one sheet of Hybond NX® nylon membrane, six strips each containing one individual sample RNA lane and one adjacent marker RNA lane were cut. Three were cross-linked with 0.24 J UV and three with EDC at 60°C for 2 h. Pairs of UV and EDC cross-linked membranes were hybridized with probes designed to detect () hsa-mir-21 and, after stripping, () hsa-mir-16. Probes were LNA or DNA oligonucleotides end-labelled with γ- P ATP or RNA transcribed with α-P UTP. Hybridizations were carried out at 40°C and blots washed in 0.2× SSC/0.2% SDS at 50°C and the image detected by phosphorimaging
Hsp90 inhibitors enhance the antitumoral effect of osimertinib and overcome osimertinib resistance in non-small cell cell lung cancer cell models
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