Identification of resistance mechanism to targeting of the ADAM 17/ EGFR axis in triple negative breast cancer in vivo
Triple-negative breast cancers (TNBCs) (ER/PR/HER2 negative) represent 15% of invasive\nbreast cancers and occur at a higher rate in young and African-American women. Exploration of\nnovel therapeutic approaches is critical, since only 30% of woman with metastatic breast cancer\nwill survive and vir...
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| Formato: | Tesis de maestría acceptedVersion |
| Lenguaje: | Inglés |
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Facultad de Farmacia y Bioquímica
2015
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| Acceso en línea: | http://repositoriouba.sisbi.uba.ar/gsdl/cgi-bin/library.cgi?a=d&c=afamaster&cl=CL1&d=HWA_835 http://repositoriouba.sisbi.uba.ar/gsdl/collect/afamaster/index/assoc/HWA_835.dir/835.PDF |
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| Sumario: | Triple-negative breast cancers (TNBCs) (ER/PR/HER2 negative) represent 15% of invasive\nbreast cancers and occur at a higher rate in young and African-American women. Exploration of\nnovel therapeutic approaches is critical, since only 30% of woman with metastatic breast cancer\nwill survive and virtually none with metastatic TNBC. The status quo as it pertains to the\ntreatment of TNBCs can be summarized as: no effective therapies available. In part, the lack of\ntherapeutic success is due to high genetic heterogeneity of TNBCs, challenging single drug\napproaches.\nMany targeted strategies to treat TNBC are being explored, including the inhibition of kinase\npathways (e.g. PI3K/Akt, MEK, VEGFR and PDGFR), the inhibition of DNA repair, of survival\npathways and androgen receptor blockade. In most cases, such single-drug targeted therapy is\ncombined with systemic genotoxic chemotherapy. For example, although about 60% of basallike\nTNBCs over express EGFR, EGFR targeted therapy, including kinase inhibition, has been\ndisappointing due to the development of resistance.\nVarious resistance mechanisms allow cancer cells to evade single-drug targeted therapies:\nmutations in the targeted molecules, extensive crosstalk/pathway redundancy and the upregulation\nof alternate growth or survival pathways. Design of combinatorial approaches of\ntherapeutics for TNBC that overcome resistance is therefore critical. The contribution of the\nproposed research is expected to be the identification of signaling network perturbations that\noccur in response to single targeted therapies, in particular in ADAM17/EGFR axis inhibition,\nand confer resistance. Based on published results, inhibition of the ADAM17/EGFR ligand axis\nin TNBC should provide therapeutic benefit with reduced tumor growth and decreased\nmetastasis, if not possibly cure.\nIn our in vitro studies on PKC? and PPP1R14D gene knockout in MDA-MB-231 cells indeed led\nto decreases in cellular growth and migration. However, to our surprise, when the same cells\nwere injected into mice through orthotropic fat pad transplantation, they produced aggressive,\nmetastatic tumors that showed activation of alternate growth signaling pathways, namely of the\nmitogen-activated protein kinase ERK and of the PI3kinase target Akt, also a mitogen activated\nkinase. This suggested that TNBC cells were developing resistance to EGF ligand regulator\nknockdown by rewiring their growth factor signaling pathways. To determine where these\nadditional growth signals come from, we first considered the tumor cells themselves.\nIn this context we discovered that when kept in culture, MDA-MB-231 cells expressing sh-\nRNAs targeting either PKCa or PPP1R14D maintained knockdown of the target for up to 35days\ntested. At the same time EGFR and ERK showed low activity as expected due to a decrease in\nEGF ligand cleavage; Akt activity was undetectable. Since we observed strong reactivation of\nERK and new activation of Akt in tumors in vivo, we considered possible up-regulation of other\ngrowth factor receptors on the cell surface that would be engaged by factors released from the\ntumor stroma once cells are inserted in vivo. Indeed, we found that FGFR2 and Erbb4 were\nupregulated. It is therefore likely that reactivation of ERK and new activation of Akt was due to\nFGFR2 and Erbb4. This would suggest that combination therapy of EGF ligand release regulator\ninhibition and FGFR inhibition would decrease growth of these tumors in vivo. |
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