Prevention of resistances to targeted therapies in lung cancer with a new therapeutic combination.

Lung cancer is the leading cause of cancer-related deaths in France and worldwide. The development of new treatments such as targeted therapies has revolutionized the therapeutic management of patients with genetic alterations in key genes involved in tumor development such as EGFR, ALK, ROS1, BRAF, or more recently KRAS. However, the effectiveness of these treatments is limited over time due to the emergence of resistance.

In this study, we aimed to decipher the origins of these resistances to increase treatment’s efficacy. We discovered that tumor cells stop dividing within the first few hours of treatment and revert to a state that mimics that of normal lung cells. However, this apparent restoration of normality is short-lived, as a small proportion of cells are able to proliferate again, thus causing relapse. This transition between the different states requires the involvement of proteins whose activity depends on the enzyme farnesyltransferase. The pharmacological inhibition of this enzyme prevents tumor cells from resisting treatment, causing their death. Therapeutic combinations involving targeted therapy and a farnesyltransferase inhibitor are currently in early-phase clinical trials and represent a real hope for reducing relapse in patients.

The combination of targeted therapy with a farnesyltransferase inhibitor represents a real hope for reducing relapse in patients and thus increasing their survival. These combinations are currently being tested in early-phase clinical trials. (www.clinicaltrials.gov; NCT06026410).

Our work provides a better understanding of the origin of resistance to targeted therapies, which could lead to the development of new therapeutic strategies, not only for lung cancer but also for other diseases.

2 patents are associated to this work, the first one for the combination of EGFR inhibitors and farnesyltransferase inhibitors, the second one for the combination of KRAS inhibitors and farnesyltransferase inhibitors.

Emergence of a clone resistant to osimertinib, an anti-EGFR targeted therapy
Lung tumor HCC827 cells that harbor an EGFR mutation, cultured in a petri dish, were genetically modified to express a cell cycle marker. The nuclei of cells blocked in the G1 phase (non-proliferative) appear red, and those of cells in the S/G2 phase (able to re-proliferate) appear green. This image was taken after 30 days of treatment with the EGFR inhibitor osimertinib, when the emergence of a small proliferative population can be observed amongst a population blocked in G1 (red), which appears to be organized into alveoli, thus resembling the normal architecture of a healthy lung.

Collaborations and partnerships

Funding :

• Inserm,
• CNRS,
• Fondation pour la Recherche Médicale (FRM, équipe labellisée [DEQ20170839117]),
• Programme de Recherche Translationnelle en Cancérologie (INCa-DGOS, [PRT-K18-048]),
• Fondation Toulouse Cancer Santé,
• Labex TOUCAN,
• Ligue Nationale Contre le Cancer,
• Fondation ARC,
• ALK+ROS1 France association de patients,
• Kura Oncology (contrat de Recherche Sponsorisée).

Collaborators :

• Antonio Maraver, Jacques Colinge, Jean-Philippe Villemin: IRCM, Montpellier
• Irene Ferrer, Luis Paz-Ares: Unidad de Investigación Clínica de Cáncer de Pulmón, Instituto de Investigación Hospital 12 de Octubre-CNIO, Madrid, Espagne
• Linda Kessler, Francis Burrows: Kura Oncology, Inc., San Diego, USA