Mécanismes moléculaires associés à la tolérance aux inhibiteurs de tyrosine kinase dans les adénocarcinomes pulmonaires

Les cancers du poumon représentent la première cause de mortalité par cancer. Des altérations génétiques au sein du gène de l’EGFR ont été identifiées comme responsable de l’émergence d’adénocarcinomes pulmonaires par un mécanisme d’hyper-activation du récepteur. Malgré le développement de thérapies ciblées (EGFR-TKI) les patients présentent une réponse partielle aux traitements, avec la persistance de cellules tumorales constituant une maladie résiduelle. Il a récemment été démontré que ces cellules tolérantes (DTP) pouvaient être un réservoir à partir duquel des cellules résistantes pouvaient émerger. Les objectifs de mon projet de thèse ont été de mettre en évidence la présence de DTP sous EGFR-TKI, d’identifier les altérations moléculaires associées et de caractériser fonctionnellement leur impact sur l’émergence de ces cellules. Les résultats acquis pendant ma thèse ont permis de caractériser d’avantage le phénotype des cellules DTP et d’identifier un groupe de sérine thréonine kinases dérégulées intervenant initialement dans la modulation du cycle cellulaire. Nous avons démontré que les DTP maintenaient la synthèse protéique de ces kinases par un mécanisme d’adaptation traductionnel permettant notamment à l’une d’entre elles, de réactiver les voies de signalisations cellulaires tel un mécanisme de compensation. L’inhibition pharmacologique de cette kinase et de l’EGFR peut réduire de la proportion de DTP et à démontrer une efficacité sur les cellules résistantes. L’identification de cette vulnérabilité des DTP représente une piste intéressante pour cibler la maladie résiduelle et retarder l’émergence de la résistance.Lung cancer is the leading cause of related cancer cell death. Activating mutations in the EGFR gene could drive in the emergence of lung adenocarcinomas through hyper-activation of the corresponding tyrosine kinase receptor. Despite the development of targeted therapies (EGFR-TKIs), patients usually respond partially to treatment and evidence persistence of tumor cells responsible for residual disease. Recently, these tolerant persiter cells (DTP) have been described as a reservoir from which drug resistant cells could emerge. The objectives my PhD project were to highlight the presence of DTPs under EGFR-TKI, to identify and functionally characterized molecular alterations associated with emergence of these cells. Thus, our results allowed to further characterize the DTP phenotype and to identify a group of dysregulated serine threonine kinases initially involved in cell cycle modulation. We demonstrated that DTP evidenced an adaptative translational mechanism responsible for maintenance of one of these kinases which could reactivate survival signaling pathways as a bypass track. Concomitant inhibition of this kinase with EGFR inhibition impacted the establishment of DTP and has also been effective on resistant cells. The identification of this DTP vulnerability constitutes an interesting candidate to target residual disease and to delay the emergence of resistance

Outcomes in oncogenic-addicted advanced NSCLC patients with actionable mutations identified by liquid biopsy genomic profiling using a tagged amplicon-based NGS assay.

Circulating tumor DNA (ctDNA)-based molecular profiling is rapidly gaining traction in clinical practice of advanced cancer patients with multi-gene next-generation sequencing (NGS) panels. However, clinical outcomes remain poorly described and deserve further validation with personalized treatment of patients with genomic alterations detected in plasma ctDNA. Here, we describe the outcomes, disease control rate (DCR) at 3 months and progression-free survival (PFS) in oncogenic-addicted advanced NSCLC patients with actionable alterations identified in plasma by ctDNA liquid biopsy assay, InVisionFirst®-Lung. A pooled retrospective analysis was completed of 81 advanced NSCLC patients with all classes of alterations predicting response to current FDA approved drugs: sensitizing common EGFR mutations (78%, n = 63) with T790M (73%, 46/63), ALK / ROS1 gene fusions (17%, n = 14) and BRAF V600E mutations (5%, n = 4). Actionable driver alterations detected in liquid biopsy were confirmed by prior tissue genomic profiling in all patients, and all patients received personalized treatment. Of 82 patients treated with matched targeted therapies, 10% were at first-line, 41% at second-line, and 49% beyond second-line. Acquired T790M at TKI relapse was detected in 73% (46/63) of patients, and all prospective patients (34/46) initiated osimertinib treatment based on ctDNA results. The 3-month DCR was 86% in 81 evaluable patients. The median PFS was of 14.8 months (12.1-22.9m). Baseline ctDNA allelic fraction of genomic driver did not correlate with the response rate of personalized treatment (p = 0.29). ctDNA molecular profiling is an accurate and reliable tool for the detection of clinically relevant molecular alterations in advanced NSCLC patients. Clinical outcomes with targeted therapies endorse the use of liquid biopsy by amplicon-based NGS ctDNA analysis in first line and relapse testing for advanced NSCLC patients

RET-MAP: An International Multicenter Study on Clinicobiologic Features and Treatment Response in Patients With Lung Cancer Harboring a RET Fusion

Nearly 1% to 2% of NSCLCs harbor RET fusions. Characterization of this rare population is still incomplete