Publication: Caracterización proteómica de la inhibición de HSP90 en el adenocarcinoma de pulmón
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2021-02-22
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Universidad Complutense de Madrid
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Abstract
Las proteínas de choque térmico (HSPs) son inducidas, en respuesta a una amplia variedad de factores fisiológicos y ambientales estresantes, permitiendo a las células sobrevivir a condiciones que de otro modo hubieran sido letales. En concordancia con ello, las HSPs se hacen esenciales en el mantenimiento de la célula tumoral, describiéndose una expresión alterada de estas proteínas en casi todos los tipos tumorales. En concreto, la sobreexpresión de HSP90 ha sido relacionada con una pobre prognosis en cáncer, debido a su capacidad para regular y estabilizar un gran número de proteínas oncogénicas, denominadas clientes de HSP90. Particularmente, en el cáncer de pulmón no microcítico (CPNM), el subtipo histológico de adenocarcinoma de pulmón presenta diversas alteraciones moleculares conductoras que son clientes de HSP90 y algunas como EGFR o EML4-ALK exhiben una fuerte dependencia de la chaperona que las hace más sensibles a los inhibidores de HSP90. Sin embargo, tal y como se ha visto en los diferentes ensayos clínicos realizados hasta la fecha en esta patología, no todos los pacientes susceptibles de ser sensibles a la inhibición de HSP90 responden positivamente al tratamiento. Por todo esto, el objetivo de esta tesis doctoral es la identificación de la firma proteica subyacente a la inhibición de HSP90, así como la búsqueda de potenciales biomarcadores de sensibilidad y respuesta, esenciales para maximizar la eficacia del tratamiento en el adenocarcinoma de pulmón...
Heat shock proteins (HSPs) are induced in response to a wide variety of physiological and environmental stress factors, allowing cells to survive conditions that would otherwise be lethal. Accordingly, HSPs become essential in the maintenance of the tumor cell and the altered expression of these proteins is described in almost all tumor types. Specifically, overexpression of HSP90 has been linked to a poor prognosis in cancer, principally due to its ability to regulate and stabilize a large number of oncogenic proteins, so-called HSP90 clients. Particularly, in the Non-Small Cell Lung cancer (NSCLC),the histological subtype lung adenocarcinoma presents various molecular alterations in gene drivers which are HSP90 clients, and some of them -such as EGFR or EML4-ALK- exhibit a strong dependence on this chaperone making them more sensitive to HSP90 inhibitors. However, not all patients liable to being sensitive to HSP90 inhibition respond positively to the treatment in clinical trials. Based on it, the objective of this Doctoral Thesis is the identification of the protein signature underlying HSP90 inhibition, as well as the search for potential biomarkers of sensitivity and response to this therapeutical strategy, essential to maximize the treatment efficacy in lung adenocarcinoma...
Heat shock proteins (HSPs) are induced in response to a wide variety of physiological and environmental stress factors, allowing cells to survive conditions that would otherwise be lethal. Accordingly, HSPs become essential in the maintenance of the tumor cell and the altered expression of these proteins is described in almost all tumor types. Specifically, overexpression of HSP90 has been linked to a poor prognosis in cancer, principally due to its ability to regulate and stabilize a large number of oncogenic proteins, so-called HSP90 clients. Particularly, in the Non-Small Cell Lung cancer (NSCLC),the histological subtype lung adenocarcinoma presents various molecular alterations in gene drivers which are HSP90 clients, and some of them -such as EGFR or EML4-ALK- exhibit a strong dependence on this chaperone making them more sensitive to HSP90 inhibitors. However, not all patients liable to being sensitive to HSP90 inhibition respond positively to the treatment in clinical trials. Based on it, the objective of this Doctoral Thesis is the identification of the protein signature underlying HSP90 inhibition, as well as the search for potential biomarkers of sensitivity and response to this therapeutical strategy, essential to maximize the treatment efficacy in lung adenocarcinoma...
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Tesis inédita de la Universidad Complutense de Madrid, Facultad de Medicina, leída el 07-10-2020