Le cancer du poumon est la principale cause de décès par cancer chez les hommes et les femmes dans le monde. Malgré les avancées majeures dans les traitements, les thérapies à base de platine restent la thérapie standard pour les patients atteints du cancer du poumon induit par la mutation KRAS. Bien que les composés de platine aient un premier effet sur ces patients, l’apparition d’une rechute constitue le principal défi au niveau clinique.Dans ce contexte, notre projet actuel vise à caractériser l’activation de la voie Notch dans la réponse aux sels de platines d’adénocarcinomes mutés pour K-Ras ainsi que son rôle dans l’acquisition de la résistance à ce traitement. Nous avons mis en évidence que la voie Notch est activée en réponse à divers agents induisant des dommages à l’ADN dans des lignées de cancer du poumon. Nous avons montré que cette activation est dépendante de la voie de checkpoint de Réponse aux Dommages de l’ADN (DDR) via ATM, ATM qui est une des principales kinases de la réponse cellulaire aux lésions de l’ADN telles que les cassures double-brin, causé notamment par la chimiothérapie conventionnelle. Parmi les nombreux substrats d’ATM en réponse à ces dommages, nous montrons un effet direct de MDM2 dans l’activation de la voie Notch en réponse aux dommages à l’ADN causé par le carboplatine. Nos données montrent une nouvelle interaction entre ATM, MDM2 et Notch, lors du traitement au carboplatine, qui pourrait jouer un rôle dans la cascade de signalisation favorisant la survie des cellules tumorales pulmonaires.En utilisant des xénogreffes dérivées de patients atteints d’adénocarcinomes du poumon, ainsi qu’un modèle cellulaire de xénogreffe résistant à la carboplatine, nous avons montré que l’association d’inhibiteurs de Notch et de MDM2 associé au traitement au carboplatine ont un effet accru sur le ralentissement de la croissance de la tumeur et sur la survie, en comparaison avec le traitement actuel de référence que représente le carboplatine.Nos résultats offrent une nouvelle possibilité de thérapie pour les adénocarcinomes de poumons mutés pour KRAS, et pourrait donc répondre à un besoin clinique urgent notamment pour contrecarrer la résistance aux chimiothérapies conventionnelles à base de sels de platine. / Lung cancer is the leading cause of cancer death among men and women worldwide. Despite the major advances in the treatments, platinum-based therapy remains the standard of care for patients affected by KRAS-driven lung cancer. Even though the platinum-compounds display an initial effect on these patients, the onset of the relapse constitutes the main challenge for the clinic. The molecular mechanisms underlying lung adenocarcinoma (LUAD) relapse are not completely elucidated yet, thus it is fundamental to understand them in order to improve survival of patients. Our data show that upon carboplatin treatment, the Notch pathway is activated in vitro. Since this effect was common for several other DNA damage insults, our driving hypothesis connected the DNA Damage Response (DDR) to the activation of the Notch pathway. Our data demonstrates that protein kinase ataxia telangiectasia-mutated (ATM) is a key mediator in the activation of the Notch pathway during DNA damage signalling. ATM is well-known as the chief mobilizer of the cellular response to the most toxic lesions to the DNA, the double-strand breaks which are also the type of damage caused by the conventional chemotherapy. Among the several substrates of ATM in response to the damage, there is the mouse double minute 2 protein (MDM2) that it is known to interact with the Notch pathway. Our data uncovered a new pathway connecting ATM, MDM2 and NICD during carboplatin treatment in LUAD cells.Using LUAD Patient-Derived Xenografts and a new generated carboplatin resistant cellular model, we show in vivo that the combination of Notch and MDM2 inhibitors with carboplatin showed a therapeutic benefit in tumour growth and survival compared to the standard of care, i.e. carboplatin.Our results can offer a new therapeutic window for KRAS-driven LUAD that become resistant to platinum-based therapy, hence tackling an urgent and unmet clinical need.

The area of systems biology evolved in an attempt to introduce mathematical systems theory principles in biology. Although we believe that all biological processes are essentially chemical reactions, describing those using precise mathematical rules is not easy, primarily due to the complexity and enormity of biological systems. Here we introduce a formal approach for modeling biological dynamical relationships and diseases such as cancer. The immediate motivation behind this research is the urgency to find a practicable cure of cancer, the emperor of all maladies. Unlike other deadly endemic diseases such as plague, dengue and AIDS, cancer is characteristically heterogenic and hence requires a closer look into the genesis of the disease. The actual cause of cancer lies within our physiology. The process of cell division holds the clue to unravel the mysteries surrounding this disease. In normal scenario, all control mechanisms work in tandem and cell divides only when the division is required, for instance, to heal a wound platelet derived growth factor triggers cell division. The control mechanism is tightly regulated by several biochemical interactions commonly known as signal transduction pathways. However, from mathematical point of view, these pathways are marginal in nature and unable to cope with the multi-variability of a heterogenic disease like cancer. The present research is possibly one first attempt towards unraveling the mysteries surrounding the dynamics of a proliferating cell. A novel yet simple methodology is developed to bring all the marginal knowledge of the signaling pathways together to form the simplest mathematical abstract known as the Boolean Network. The malfunctioning in the cell by genetic mutations is formally modeled as stuck-at faults in the underlying Network. Finally a mathematical methodology is discovered to optimally find out the possible best combination drug therapy which can drive the cell from an undesirable condition of proliferation to a desirable condition of quiescence or apoptosis. Although, the complete biological validation was beyond the scope of the current research, the process of in-vitro validation has been already initiated by our collaborators. Once validated, this research will lead to a bright future in the field on personalized cancer therapy.