Title: Tackling tumor resistance in lung cancer

Theme: Our team focuses on lung cancer through basic and translational studies. My presentation will cover the preclinical models used to study the lung cancer therapies we are currently developing in the laboratory, as well as our latest study that demonstrated resistance mechanisms to Smad3 inhibitors.

Key words: lung cancer, small cell lung cancer, circulating tumor cells, immunotherapy, microbiota, inhibitors, MCT1, metabolism, cholesterol

 

Dr. Rémy Pedeux is a senior INSERM research scientist and team leader at INSERM U1242 in Rennes, France, where he heads the "Adaptative Stress & Tumor EnviRonment" (ASTER) team. His research focuses on tumor suppressor genes, DNA repair, and genome stability. In recent years, he has been studying the mechanisms of resistance to targeted therapies and developing preclinical models to investigate the response to immunotherapy and the role of the microbiota. 

Rémy earned his PhD in Biochemistry from Université Claude Bernard (Lyon I), where he studied melanocyte responses to UV irradiation. He completed a postdoctoral fellowship at the National Cancer Institute (USA), contributing to the discovery and characterization of ING tumor suppressor genes. Since 2010, he has been an INSERM investigator, leading projects on cancer biology, mechanisms of tumor suppression and DNA repair. 

Dr. Pedeux is also involved in scientific committees, he is the current president of the scientific council of Biogenouest, and he collaborates with international laboratories in Canada and India. His work bridges fundamental biology and translational research, aiming to advance understanding and treatment of cancer. 

Our team focuses on small cell lung cancer by following three lines of research: firstly i) the study of liquid biopsies and in particular Circulating Tumor Cells (CTC) in order to better understand the evolution of the disease, ii) the development of relevant preclinical models to evaluate innovative treatments and finally iii) the study of the mechanisms responsible for resistance to treatments.
I will present two ongoing projects:
- the MESHCAP project focuses on developing a new, innovative murine preclinical model combining i) a controlled microbiota environment, ii) a human immune system, and iii) tumor cells from lung cancer patients. This model will provide a new solution for evaluating the efficacy of immunotherapy strategies, alone or in combination. Furthermore, the generated sub-models, which include mice with a controlled microbiota and/or a human immune system, will be used as study models to investigate the cross relationships between the microbiota and immune system.
- as non-genetic resistance remains a critical challenge in cancer therapy we used CRISPR-based activation and knockout screens to identify MCT1 as a key driver of resistance to the SMAD3 inhibitor, SIS3 in BRAF-mutated melanoma and KRAS-mutated lung adenocarcinoma. MCT1 regulates metabolic reprogramming by enabling switch between oxidative phosphorylation (OXPHOS) and glycolysis and supporting anabolic pathways like lipid and cholesterol biosynthesis. Pharmacological or genetic inhibition of MCT1 impairs tumor cell viability under SIS3 treatment both in vitro and in preclinical models. This work highlights the therapeutic potential of targeting MCT1-dependent metabolic pathways to overcome drug resistance.