BOLERO

Lung cancer patients that harbor oncogenic mutations in BRAF are treated with targeted therapies and present tumor responses that are mostly partial, ultimately followed by resistance to therapy within about 10 months. The very limited knowledge on the molecular mechanisms that promote resistance to therapy in these patients has hampered the development of subsequent therapeutic strategies to improve their survival. Besides, the current lack of pertinent BRAF-mutant NSCLC pre-clinical models has hindered the study precision medicine pre-clinical approaches to tackle therapy resistance in this context. Based on long histories of collaboration, scientific expertise and unique institutional resources, we recently initiated the BOLERO consortium, which assembles basic researchers, translational scientists and thoracic oncologists that are actively engaged in innovative and multidisciplinary lung cancer research, in high-level research institutes and some top academic medical centers in Europe. The goal of BOLERO is to integrate the scientific and clinical expertise currently available among individual partner institutes, to translate it into discoveries that might improve the survival of BRAF-mutant lung cancer patients. In this research program, we propose to capitalize on our current synergy 1) to pre-clinically model the impact of genomic alterations in effectors of the MAPK and PI3K pathways in sensitivity to BRAF-targeted therapies; 2) to generate clinically relevant patient-derived models, as well as knock-in mouse models of BRAF-mutant NSCLC, that will serve to identify therapeutic rationales to revert resistance to BRAF-targeted therapies; and 3) to assess the potential role of epithelial-to-mesenchymal transition and lineage plasticity in resistance to targeted therapies, by transcriptomic and immunohistochemistry analyses of tumor samples from BRAF-driven NSCLC. With this research program, we will identify molecular vulnerabilities that might subsequently translate into therapeutic rationales to delay or revert the emergence of resistance to therapy in BRAF-mutant lung cancer patients. To increase our competitiveness for the World Cancer Research grants, we plan to utilize the potential MRSEI ANR funding 1) to establish the Consortium and Data/Material Transfer Agreements to ensure the integration of patient samples and the associated clinical information; 2) to hold scientific meetings to define the scientific and economic strategies for the implementation of the research program, promote the coherence of the group and stimulate collaboration among the investigators; and 3) develop a web-based, integrated database to gather the molecular and clinical information of the tumour samples collected at the participating institutions of the Consortium, as well as the patient-derived models generated by the BOLERO investigators. This joint strategy streamline research efforts, decrease costs and facilitate connections with the communities of lung cancer research and clinical management. To our knowledge, BOLERO is the first consortium in the lung cancer community dedicated to study BRAF-mutant NSCLC. Overall BOLERO will promote the discovery of precision medicine approaches to prolong the survival of BRAF-mutant lung cancer patients.