Selective killing of Ras-malignant tisues by exploiting oncogene-induced DNA damage = Eliminación selectiva de tejidos malignos dependientes de RAS mediante la explotación del daño en el ADN inducido por oncogenes
[eng] Most human solid tumors present signs of genomic instability. Activated oncogenes have been proposed to induce genomic instability through the generation of replicative stress. In this thesis, we have sown that the expression of a constitutively active form of RAS oncogene promotes accelerated...
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| Tipo de recurso: | tesis doctoral |
| Estado: | Versión publicada |
| Fecha de publicación: | 2019 |
| País: | España |
| Institución: | Universidad de Barcelona |
| Repositorio: | Dipòsit Digital de la UB |
| OAI Identifier: | oai:diposit.ub.edu:2445/147220 |
| Acceso en línea: | https://hdl.handle.net/2445/147220 http://hdl.handle.net/10803/668212 |
| Access Level: | acceso abierto |
| Palabra clave: | Oncogens Apoptosi Càncer Oncogenes Apoptosis Cancer |
| Sumario: | [eng] Most human solid tumors present signs of genomic instability. Activated oncogenes have been proposed to induce genomic instability through the generation of replicative stress. In this thesis, we have sown that the expression of a constitutively active form of RAS oncogene promotes accelerated G1/S transition which leads to replicative stress and genomic instability. The resulting DNA damage present in these cells should activate the DDR response, however, RasV12 cells impair DNA damage signaling. Furthermore, RasV12 expression inhibits apoptosis through ERK. RAS is one of the most commonly mutated oncogenes, yet efficient therapies to treat RAS dependent tumors are still lacking. With this in mind, and based on our previous results, we decided to try to exploit the DNA damage present in these cells to selectively target them. In order to do so, we induced extra DNA damage with ionizing radiation and depleted ERK to promote the death of the cells. We used this strategy on RAS dependent tumors both benign and malignant tumors, and successfully targeted and killed tumor cells. We propose that MEK inhibitors, that are being used in the treatment of metastatic melanomas, could be combined with radiation to improve the therapeutic outcomes. Aside from the previously described autonomous effects, we have also observed that RasV12 expression in the wing imaginal discs induces a non-autonomous phenotype. Wild type cells adjacent to RAS cells display signs of DNA damage, apoptosis and autophagy. The role of these non-autonomous effects is not clear; however, we hypothesize that they may play a role in metabolically supporting tumor growth. |
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