Lung cancer is the leading cause of cancer death worldwide, with over two million people diagnosed annually, including more than 50,000 in France. Over the last decade, translational research and clinical trials have led to the emergence of targeted therapies for genomic alterations, alongside the development of immunotherapy. The concept of personalized or precision medicine has brought new hope to patients with advanced-stage (IIIB/IV) and, more recently, early-stage (IA-IIIA) cancer. Despite these advances, the 5-year survival rate for non-small cell lung cancer (NSCLC) remains below 5% in advanced stages, and one in two patients will die from their cancer within five years of surgery for early-stage disease.
NSCLC accounts for 85-90% of all lung cancers, with adenocarcinomas representing 40-50% of cases. Among these, 30-40% carry a KRAS mutation, representing a major therapeutic target. KRAS, évoquant une cible thérapeutique majeure.
Although discovered in 1982, KRAS mutation was long considered "undruggable." The 2021 FDA approval of the first drug targeting a KRASmutation marked a breakthrough for KRAS G12CNSCLC patients. These KRAS inhibitors are currently administered as second-line treatment in patients who progress after receiving chemotherapy, immunotherapy or a combination of immunotherapy and chemotherapy. Despite the emergence of these inhibitors, a large number of KRAS -mutated NSCLCs are currently administered as second-line treatment in patients who progress after receiving chemotherapy, immunotherapy or a combination of immunotherapy and chemotherapy. Despite the emergence of these inhibitors, a large number of mutated NSCLCs.
Les CPNPC mutés KRAS -mutated NSCLCs are mainly caused by smoking, leading to tumours with a high mutational burden. An increased mutational burden is thought to confer a good response to immunotherapies, including treatments with immune checkpoint inhibitors (anti-PD-1/PDL-1). However, the presence of alterations in certain genes (e.g. STK11, KEAP1 or SMARCA4) may reduce the response to immunotherapies in KRAS-mutated NSCLCs, due, among other things, to reduced lymphocyte infiltration and an immunosuppressive tumour microenvironment.
In recent years, one of the new hopes in oncology has been the implementation of treatments combining an antibody, capable of identifying cancer cells, with an associated cytotoxic drug, which can be delivered directly to the heart of the targeted tumor cell. These antibody-drug conjugates (ADCs) offer a two-fold advantage: the ability to destroy cancer cells using more potent cytotoxic doses than conventional chemotherapy, while simultaneously sparing healthy cells.
Clinico-pathological knowledge regarding KRAS mutations in early stages is currently very limited, as are the associated genomic alterations, the expression of various immune checkpoints, and the expression of targets for antibody-drug conjugates. This knowledge is essential to optimize the selection of patients eligible for personalized treatments targeting KRASmutations, particularly KRASG12C.
Finally, detecting lung cancer as early as possible remains a major objective, and many tools, including Artificial Intelligence, appear promising. In 2023, researchers from the Massachusetts Institute of Technology in Cambridge trained and validated a new algorithm on thousands of chest CT scans to predict the risk of developing lung cancer within six years of the scan. However, for KRAS, -mutated NSCLC, studies to develop predictive algorithms from medical imaging or histological sections of tumor tissue are scarce and warrant initiation.
This project is therefore part of a global movement towards more personalized and predictive medicine.
The project "Characterization of KRASG12C -mutated NSCLC: from epidemio-clinico-pathological profile to associated proteogenomic alterations" aims to develop and implement a holistic approach combining high-performance macroscopic, microscopic, and molecular tools to characterize KRAS-mutated NSCLC. The goal is to optimize the selection of patients eligible for personalized treatments targeting KRASmutations, particularly KRASG12C.
The primary objective of this project is to determine whether KRASG12C is associated with co-mutations and/or the overexpression of certain protein markers, which may hold prognostic value and/or predictive value for therapeutic response.
Two complementary objectives are also pursued:
Beyond these objectives, the project also aims to identify a KRAS signature from medical imaging or histological sections of tumor tissue, thereby simplifying the diagnosis of KRAS -mutated NSCLC for faster clinical management.
The in-depth analysis of individual profiles will allow for the identification of patient subgroups carrying markers with prognostic and/or predictive value for therapeutic response. This process involves collecting tumor tissues from individuals with KRAS -mutated NSCLC and consolidating the associated clinical data.
To achieve these ambitious goals, the project relies on an innovative combination of advanced technologies in molecular and protein analysis.
The scientific approach is based on several complementary and innovative tools:
The success of this project is built on close collaboration between various academic and industrial partners:
This synergy between fundamental research, clinical practice, and cutting-edge technology ensures a comprehensive and innovative approach, maximizing the project's chances of success.
This project paves the way for major research dedicated to patients with KRAS-mutated non-small cell lung cancer (NSCLC). This holistic approach is groundbreaking for this patient population and marks a significant step toward more targeted medicine, focused on the co-expression of genes and developing therapeutic targets.
One of the major expected benefits is the re-evaluation of certain patients carrying the KRAS mutation, through a precise and exhaustive characterization of early stages, which, to date, have been understudied compared to advanced stages. By optimizing the selection of patients eligible for personalized treatments targeting KRASmutations, this project aims to substantially improve the quality of life and prognosis for this patient population.
This integrative pathology approach, which combines various fields, will generate a coherent model for understanding and predicting the disease, as well as understanding treatment response in patients with KRAS.
Through this project, IHU RespirERA affirms its commitment to a proactive approach to respiratory health, focusing on innovative research, a holistic perspective, and personalized, patient-centered care. This innovative approach represents a major milestone in durably improving respiratory health and patient quality of life, while optimizing the use of medical resources.
