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Etude Des Résistances Adaptatives Aux Inhibiteurs De Tyrosine Kinase De L’EGFR Dans Les Cancers Bronchiques

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Etude Des Résistances Adaptatives Aux Inhibiteurs De Tyrosine Kinase De L’EGFR Dans Les Cancers Bronchiques Thèse d’exercice Faculté de Pharmacie Année 2020 Thèse N° MÉMOIRE DU DIPLÔME D'ÉTUDES SPÉCIALISÉES D’INNOVATION PHARMACEUTIQUE ET RECHERCHE TENANT LIEU DE THÈSE D’EXERCICE POUR LE DIPLÔME D’ÉTAT DE DOCTEUR ENPHARMACIE Présentée et soutenue publiquement le 24 septembre 2020 par Sarah FIGAROL Née le 19 septembre 1989 à Toulouse Etude des résistances adaptatives aux inhibiteurs de tyrosine kinase de l’EGFR dans les cancers bronchiques Thèse dirigée par Gilles Favre Examinateurs : M. Franck Saint-Marcoux, président du jury M.Gilles Favre, directeur de thèse M. Jean-Marie Canonge, juge M. Julien Mazières, juge M. Antonio Maraver, juge Thèse d’exercice Faculté de Pharmacie Année 2020 Thèse N° MÉMOIRE DU DIPLÔME D'ÉTUDES SPÉCIALISÉES D’INNOVATION PHARMACEUTIQUE ET RECHERCHE TENANT LIEU DE THÈSE D’EXERCICE POUR LE DIPLÔME D’ÉTAT DE DOCTEUR ENPHARMACIE Présentée et soutenue publiquement le 24 septembre 2020 par Sarah FIGAROL Née le 19 septembre 1989 à Toulouse Etude des résistances adaptatives aux inhibiteurs de tyrosine kinase de l’EGFR dans les cancers bronchiques Thèse dirigée par Gilles Favre Examinateurs : M. Franck Saint-Marcoux, président du jury M.Gilles Favre, directeur de thèse M. Jean-Marie Canonge, juge M. Julien Mazières, juge M. Antonio Maraver, juge Sarah FIGAROL | Thèse d’exercice | Université de Limoges |2020 3 Licence CC BY-NC-ND 3.0 Liste des enseignants Le 1er septembre 2019 PROFESSEURS : BATTU Serge CHIMIE ANALYTIQUE CARDOT Philippe CHIMIE ANALYTIQUE ET BROMATOLOGIE DESMOULIERE Alexis PHYSIOLOGIE DUROUX Jean-Luc BIOPHYSIQUE, BIOMATHEMATIQUES ET INFORMATIQUE FAGNERE Catherine CHIMIE THERAPEUTIQUE - CHIMIE ORGANIQUE LIAGRE Bertrand BIOCHIMIE ET BIOLOGIE MOLECULAIRE MAMBU Lengo PHARMACOGNOSIE ROUSSEAU Annick BIOSTATISTIQUE TROUILLAS Patrick CHIMIE PHYSIQUE - PHYSIQUE VIANA Marylène PHARMACOTECHNIE PROFESSEURS DES UNIVERSITES - PRATICIENS HOSPITALIERS DES DISCIPLINES PHARMACEUTIQUES : PICARD Nicolas PHARMACOLOGIE ROGEZ Sylvie BACTERIOLOGIE ET VIROLOGIE SAINT-MARCOUX Franck TOXICOLOGIE ASSISTANT HOSPITALIER UNIVERSITAIRE DES DISCIPLINES PHARMACEUTIQUES : CHAUZEIX Jasmine HÉMATOLOGIE JOST Jérémy PHARMACIE CLINIQUE MAITRES DE CONFERENCES : BASLY Jean-Philippe CHIMIE ANALYTIQUE ET BROMATOLOGIE BEAUBRUN-GIRY Karine PHARMACOTECHNIE BÉGAUD Gaëlle CHIMIE ANALYTIQUE ET CONTRÔLE DU MÉDICAMENT Sarah FIGAROL | Thèse d’exercice | Université de Limoges |2020 4 Licence CC BY-NC-ND 3.0 BILLET Fabrice PHYSIOLOGIE CALLISTE Claude BIOPHYSIQUE, BIOMATHEMATIQUES ET INFORMATIQUE CHEMIN Guillaume BIOCHIMIE CLÉDAT Dominique CHIMIE ANALYTIQUE ET BROMATOLOGIE COMBY Francis CHIMIE ORGANIQUE ET THERAPEUTIQUE COURTIOUX Bertrand PHARMACOLOGIE, PARASITOLOGIE DELEBASSÉE Sylvie MICROBIOLOGIE-PARASITOLOGIE- IMMUNOLOGIE DEMIOT Claire-Elise PHARMACOLOGIE FABRE Gabin SCIENCES PHYSICO-CHIMIQUES ET INGÉNIERIE APPLIQUÉE FROISSARD Didier BOTANIQUE ET CRYPTOGAMIE JAMBUT Anne-Catherine CHIMIE ORGANIQUE ET THERAPEUTIQUE LABROUSSE Pascal BOTANIQUE ET CRYPTOGAMIE LAVERDET Betty PHARMACIE GALÉNIQUE LEGER David BIOCHIMIE ET BIOLOGIE MOLÉCULAIRE MARRE-FOURNIER Françoise BIOCHIMIE ET BIOLOGIE MOLÉCULAIRE MERCIER Aurélien PARASITOLOGIE MILLOT Marion PHARMACOGNOSIE MOREAU Jeanne MICROBIOLOGIE-PARASITOLOGIE- IMMUNOLOGIE PASCAUD-MATHIEU Patricia PHARMACIE GALENIQUE – BIOMATÉRIAUX CERAMIQUES POUGET Christelle CHIMIE ORGANIQUE ET THÉRAPEUTIQUE VIGNOLES Philippe BIOPHYSIQUE, BIOMATHÉMATIQUES ET INFORMATIQUE Sarah FIGAROL | Thèse d’exercice | Université de Limoges |2020 5 Licence CC BY-NC-ND 3.0 ATTACHE TEMPORAIRE D’ENSEIGNEMENT ET DE RECHERCHE : BOUDOT Clotilde MICROBIOLOGIE (du 01/09/2018 au 31/08/2020) MARCHAND Guillaume CHIMIE ORGANIQUE ET THÉRAPEUTIQUE (du 01/09/2019 au 31/08/2020) PROFESSEURS EMERITES : DREYFUSS Gilles (jusqu’au 31/03/2020) Sarah FIGAROL | Thèse d’exercice | Université de Limoges |2020 6 Licence CC BY-NC-ND 3.0 Remerciements Aux membres de mon jury. Je tiens à adresser mes remerciements au Pr Franck Saint-Marcoux pour avoir accepté de présider ma thèse ainsi qu’au Pr Jean-Marie Canonge, au Pr Julien Mazières et au Dr Antonio Maraver pour avoir accepté d’évaluer mon travail de thèse. À mon directeur de thèse. Merci au Pr Gilles Favre de m’avoir accueillie dans son équipe, de m’avoir donné les moyens de faire avancer mon projet de thèse dans des conditions idéales et d’avoir toujours su porter un regard d’ensemble sur le projet de thèse et les orientations à lui donner. À Olivier et Anne. Je remercie énormément le Dr Olivier Calvayrac, mon parrain de la Science, pour m’avoir tout appris et transmis, du western blot à la rédaction d’un papier. Merci de ton implication quotidienne dans le projet et ma thèse ainsi que pour ton grand optimisme qui m’a toujours donné du courage. Merci au Dr Anne Pradines pour sa disponibilité sans faille et sa bienveillance, pour tous ses coups de pouce qui ont permis de débloquer, recentrer, faire avancer les choses, ainsi que pour la rigueur qu’elle m’a apportée. À toutes les personnes qui ont participé à ce travail. Merci Rémi, pour tout le travail que tu as fourni pour m’aider dans les manips et surtout pour les nombreuses mises au point techniques que tu as effectuées. Merci Raghda pour la grande aide que tu m’as apportée pour la qPCR, tu es indéniablement devenue une spécialiste en la matière. Merci Célia pour prendre mon relais pour la suite des manips et pour le travail que tu es en train d’effectuer pour générer les cellules KO avec Isa que je remercie également. Je n’ai aucun doute sur le fait qu’avec vous je laisse la suite du projet entre de bonnes mains. Merci Claudine pour les ELISA. Merci Anne Casa pour ton aide pour les dd-PCR et la confection des librairies. Merci Estelle pour le marquage Beta-Gal vivo. Merci Sandra pour la génération des cellules GFP et des DTEC, ainsi que pour m’avoir aidée, remplacée dès que j’en ai eu besoin, je citerai en particulier mon épisode coronavirus-like et la fois où mon pouce avait malencontreusement trop trempé dans l’azote. Merci également aux stagiaires, Ayman et Marie, pour leur contribution au projet. Merci aux services supports et au pôle technologique du CRCT. Merci Laetitia pour l’incucyte, merci Manon pour le tri cellulaire, merci Karine et Marie pour les expérimentations de transcriptomique et leurs analyses. Merci à nos collaborateurs à Montpellier, Antonio Maraver, Jacques Colinge et leurs équipes. À tous les membres passés et présents de l’équipe 3. Merci Sandra pour ton soutien inconditionnel et pour tous les moments qu’on a partagés. Evidemment, et tu le sais, je te souhaite beaucoup de réussite pour ta thèse et pour la suite, accroche-toi et n’oublie pas de garder en tête tes objectifs et d’avoir confiance en toi et en tes capacités. Merci Rémi pour tes blagues pourries, j’ai essayé de prendre exemple mais tu es indétrônable à ce niveau. Plus sérieusement, j’ai énormément apprécié travailler avec toi et ne te souhaite que de bonnes choses pour ta vie personnelle et ta poursuite de carrière. Merci Claire pour notre point quotidien trafic SNCF/vie à la campagne, nos discussions et ta bienveillance envers moi. Sarah FIGAROL | Thèse d’exercice | Université de Limoges |2020 7 Licence CC BY-NC-ND 3.0 Merci Claudine, maman du labo et petite-routarde de la Crète, pour ta bonne humeur, c’est très agréable de travailler à tes côtés. Merci Isa de m’avoir donné le goût de l’enseignement, tu es une super prof et la pédagogie que tu emploies avec tes étudiants est exemplaire. Merci Faten, Laetitia, Magda et Simona pour m’avoir montré le chemin du doctorat, vous avez toutes été des exemples pour moi. Sébastian et Mathéa, tout comme Sandra, je vous souhaite beaucoup de réussite pour votre thèse. Merci à tous les autres membres de l’équipe, Patrick, Olivier S., Stéphanie, Aurélien, Delphine, Célia, Nésibé, Raghda, Agnese et Anaïs, ainsi qu’aux stagiaires, passés et présents. Les discussions scientifiques et extra-scientifiques que nous avons pu avoir m’ont fait grandir et ont rendu ma vie au labo très agréable. J’ai adoré ces années passées au labo avec vous, je sais bien qu’il faut partir vers d’autres horizons, couper le cordon, mais vous allez me manquer. Je souhaite le meilleur au niveau professionnel et personnel à chacun d’entre vous. À mes amis du lycée et de la fac. Merci cousine Laure pour avoir toujours été à mes côtés, m’avoir toujours conseillée et me connaître mieux que quiconque. Merci mes potes du lycée, Laure, Julien, Joël, Finette, Théo, Romain, Paul et les autres, pour m’avoir forgé un caractère de « teigne », je pense que ça m’a bien aidée dans la réalisation de cette thèse. Je suis heureuse et chanceuse de continuer à vous voir régulièrement et d’être témoin de nos progressions respectives dans la vie depuis qu’on se connait. Merci mes copines de la fac, Julie, Mayka, Camille et aussi Emilie pour m’avoir accompagnée durant les années pharma et tous les moments qu’on a passés ensemble. On peut dire qu’enfin, et ce n’est pas trop tôt, avec cette thèse, je conclue nos années pharma. Je suis ravie de continuer à vous voir souvent et qu’on continue à partager des choses. À ma famille. Je remercie grandement mes parents pour m’avoir tout donné, pour m’avoir toujours soutenue et pour m’avoir transmis la valeur du travail. Je remercie également mes frères et ma sœur, pour leur présence bienveillante dans ma vie et pour m’avoir supporté en tant que petite dernière. Je vous dis un grand merci et suis consciente de la chance que j’ai de vous avoir dans ma vie. J’adresse une pensée toute particulière à mes grands-parents, je leur dis que j’aurais aimé leur raconter tout ça et les remercie pour l’exemple qu’ils m’ont donné. Je remercie également mes belles-familles. Merci Claudie et Jérôme, Bertrand et Angéline, Thibault et Anaïs, pour l’intérêt et le soutien que vous nous manifestez, à Clément et moi.
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