93 research outputs found
STAT3 as a potential immunotherapy biomarker in oncogene-addicted non-small cell lung cancer
No full textImmune checkpoint blockade has modified the treatment landscape for many types of tumors, including lung cancer. Still our knowledge on the biology of the interaction between tumor cells and the microenvironment is limited, preventing the optimal use of these new compounds and the maximum benefit that the patients can derive from them. We have actively worked on the role of STAT3, a transcriptional factor that causes innate resistance to targeted therapies in oncogene-addicted tumors. In this short review we take the opportunity to express our opinion and review existing knowledge on the immune role of STAT3 and the possible implications that this may have for the discovery of new biomarkers to predict response to immunotherapy, as well as new partners to combine with and increase the efficacy of immune checkpoint inhibitors
Abstract 3077: Tumor cells with acquired resistance to EGFR inhibitors and overexpression or activation of AXL, MET and FGFR1 are insensitive to single-agent treatment targeting AXL, MET or FGFR
No full textAbstract
Background: Aberrant activity of the MET, FGFR1 and AXL receptors has been associated with the development of resistance to first, second and third generation EGFR tyrosine kinase inhibitors (TKI) in EGFR-mutated non-small cell lung cancer (NSCLC) patients.
Methods: We obtained 6 resistant lines by treating EGFR-mutated (exon 19), TKI sensitive PC9 cells with increasing concentrations of gefitinib or erlotinib. The p.T790M resistance mutation emerged in two cell lines (GR1, GR4), which remained sensitive to osimertinib, a third generation EGFR TKI. Six new cell lines to resistant to “second line” osimertinib were generated from GR1 and GR4 by exposure to increasing concentrations of the inhibitor. Finally, six more cell lines resistant to “first line” osimertinib were derived from the PC9 parental cells. All resistant cell lines were genotyped for selected genes (including EGFR) and characterized for AXL, MET and FGFR1 expression and activation by Q-RT-PCR, immunohistochemistry and Western blotting. The effects of AXL (BGB324), MET (crizotinib, capmatinib) and FGFR1 (nindetanib) inhibitors on the parental and the 18 resistant cell lines were analyzed by MTT and, in some cases, by colony formation. AXL was stably silenced in some of the resistant cell lines.
Results: All cell lines resistant to “first line” gefitinib, erlotinib and osimertinib maintained the exon 19 EGFR sensitizing mutation. In contrast, three of the resistant cell lines to “second line” osimertinib lost the exon 19 and the p.T790M mutations. In two more, the p.T790M dropped to low allelic fractions (1% and 0.03%). Regardless of the EGFR status, AXL overexpression was the most common event related to EGFR TKI resistance in our panel of 18 cell lines, with FGFR1 and MET overexpression or activation as less frequent events. In proliferation assays, the IC50 of the EGFR TKI resistant cell lines for BGB324 (AXL inhibitor) was indistinguishable from the IC50 of the parental, EGFR TKI sensitive cell line. Similar results were obtained in the case of capmatinib, crizotinib (MET inhibitors) and nintedanib (FGFR inhibitor). Stable silencing of AXL on some of the AXL-overexpressing resistant cell lines had no effects in terms of doubling times, morphology of cells or sensitivity to EGFR TKIs. In combination experiments, the effect of BGB and MET inhibitors was found to be additive.
Conclusions: In tumor cell line models of acquired resistance to EGFR TKIs, overexpression or activation of AXL, MET and FGFR1 was not associated to sensitivity to single-agent treatment with AXL, MET or FGFR inhibitors. Multitargeted approaches might be more effective in this setting.
Citation Format: Jordi Bertran-Alamillo, Miguel Angel Molina-VIla, Cristina Teixidó, Jordi Codony-Servat, Ana Giménez-Capitán, Carles Codony-Servat, Silvia García-Román, Erika Aldeguer, Sonia Rodríguez, Rafael Rosell. Tumor cells with acquired resistance to EGFR inhibitors and overexpression or activation of AXL, MET and FGFR1 are insensitive to single-agent treatment targeting AXL, MET or FGFR [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3077. doi:10.1158/1538-7445.AM2017-3077</jats:p
Co-activation of STAT3 and YES-Associated Protein 1 (YAP1) Pathway in EGFR-Mutant NSCLC
No full textThe efficacy of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in EGFR-mutant non-small cell lung cancer (NSCLC) is limited by adaptive activation of cell survival signals. We hypothesized that both signal transducer and activator of transcription 3 (STAT3) and Src-YES-associated protein 1 (YAP1) signaling are dually activated during EGFR TKI treatment to limit therapeutic response
Don Francisco Codony de Paladella, coronel de los Reales Exercitos de S.M., Gobernador militar y político de esta ciudad de Manresa ... Con fecah de 9 del corriente me dice el señor fiscal de Real Sala del Crimen lo siguiente. ... En el dia 21 de este mes
No full textA monoclonal antibody that specifically recognizes m6A nucleoside
No full textA hybridoma against the nucleoside m6A has been obtained from mouse spleen. This hybridoma was named H65 and it secretes monoclonal antibodies anti-m6A. The competition assays showed that the monoclonal antibody was highly specific for m6A nucleoside.This work was supported by PGC grant no PB92-0004. C. Codony was recipient of a fellowship from PGC.Peer Reviewe
A second-step splicing activity is conserved from yeast to human
No full textWe describe a defective HeLa nuclear extract which is particularly deficient in step 2 of splicing reaction. With this extract we have studied the conservation of a second-step activity from yeast to human cells. We detected a S. cerevisiae second-step splicing activity that allows restoration of step 2 of the defective HeLa nuclear extract, which indicates that yeast purified fraction has a second-step activity that is conserved from yeast to human cells. The activity is a yeast UsnRNP protein(s) since it is purified with anti-tri-methylguanosine by immunoaffinity columns.This work was supported by PGC Grant No. PB92-0004 and an Alexander von Humboldt Foundation grant. C. Codony was the recipient of a fellowship from PGC; R.B. Cicarelli was the recipient from a fellowship from CAPES and Spanish MEC; A. Khaouja was the recipient of a fellowship from the Moroccan government.Peer Reviewe
Abstract 336: S49076, a kinase inhibitor of AXL, MET and FGFR with strong, selective preclinical activity against tumor cells with acquired resistance to EGFR inhibitors not carrying the T790M mutation
No full textRNA secondary structure mediates alternative 3′ss selection in Saccharomyces cerevisiae
No full textAlternative splicing is the mechanism by which different combinations of exons in the pre-mRNA give rise to distinct mature mRNAs. This process is mediated by splicing factors that bind the pre-mRNA and affect the recognition of its splicing signals. Saccharomyces species lack many of the regulatory factors present in metazoans. Accordingly, it is generally assumed that the amount of alternative splicing is limited. However, there is recent compelling evidence that yeast have functional alternative splicing, mainly in response to environmental conditions. We have previously shown that sequence and structure properties of the pre-mRNA could explain the selection of 3′ splice sites (ss) in Saccharomyces cerevisiae. In this work, we extend our previous observations to build a computational classifier that explains most of the annotated 3′ss in the CDS and 5′ UTR of this organism. Moreover, we show that the same rules can explain the selection of alternative 3′ss. Experimental validation of a number of predicted alternative 3′ss shows that their usage is low compared to annotated 3′ss. The majority of these alternative 3′ss introduce premature termination codons (PTCs), suggesting a role in expression regulation. Furthermore, a genome-wide analysis of the effect of temperature, followed by experimental validation, yields only a small number of changes, indicating that this type of regulation is not widespread. Our results are consistent with the presence of alternative 3′ss selection in yeast mediated by the pre-mRNA structure, which can be responsive to external cues, like temperature, and is possibly related to the control of gene expression. Copyright © 2012 RNA Society.E.E. and M.P. were supported by the Spanish Ministry of Science (MICINN) with grants BIO2008-01091, BIO2011-23920, and CSD2009-00080. The work from M.P. was also partly funded by Spanish National Health Institute Carlos III. J.V. and C.C.S. were supported by BIO2008-363 (MICINN) and by CSIC-200920I195. P.G.F. was supported by SFRH/BPD/42003/2007 (FCT-PORTUGAL) and by CSD2007-1500005 (MICINN).Peer Reviewe
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
Don Francisco Codony de Paladell, coronel de infanteria, governador militar y politico de esta ciudad de Manresa ... El Señor secretario del Real Consejo me ha pasado de orden de dicho Tribunal Supremo ... Vosotros habeis obedecido con lealtad la más exacta por espacio de veinte años al augusto monarca de las Españas ...
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