The latest advances in lung cancer research focus on improving treatments for two molecular subtypes of the disease, patients with BRAFV600E and KRASG12C mutations, who often develop resistance to current treatments. Two studies, published in the scientific journals Cell Reports and Nature Communications, and which counted on the collaboration of IDIBELL and ICO Drs Alberto Villanueva and Ernest Nadal research groups, provide new strategies that could offer more effective options for these patients. In fact, in conducting both studies, the advanced preclinical models generated through patient biopsies and also the cell lines derived from PDOXs (patient-derived orthoxenografts generated in animal models) created by professionals from IDIBELL and ICO had a key role because they have been fundamental to validate the potential therapeutic approaches indicated by the results.
Therapeutic combinations open the door to new treatments
In the case of tumours with a BRAFV600E mutation, the usual treatment consists of a combination of the drugs dabrafenib and trametinib, which block the RAF and MEK kinases. Although this treatment prolongs survival when compared to single-agent therapies, disease progression seems inevitable. In the study published in Cell Reports, the research team has used the CRISPR technique and RNA sequencing to identify vulnerabilities in persistent and drug-resistant cells obtained from PDOX. Researchers could observe that, due to the oxidative stress caused by the dabrafenib/trametinib treatment, these persistent and resistant cells become more sensitive to ferroptosis, a type of cell death due to the inability to neutralize oxidative stress caused by iron accumulation in the cell. This sensitivity proposes new therapeutic avenues to address these resistances, including the use of histone deacetylase inhibitors (HDACs) or GPX4, molecules that, by temporarily extending oxidative stress in the cell, promote cell death and improve the response to treatment.
On the other hand, lung cancers related with the KRASG12C oncogene have been treated with selective inhibitors, such as sotorasib and adagrasib, which block this oncogene in its inactive state. Even so, many patients develop resistance to these treatments through the appearance of KRASG12C mutations. This new study, published in Nature Communications, has discovered that, in addition to acquired mutations, disease progression can also be caused by adaptive mechanisms that increase the KRAS load in its active state within the cell, while acquiring tolerance to treatment by selective inhibitors. Thus, researchers propose a new therapeutic strategy: an inhibitor that attacks KRAS in its active state, called RMC-6291. The preclinical analyses results, carried out thanks to the abovementioned PDOXs, suggest that the combination of this drug with inhibitors of the inactive state may be a promising alternative to overcome sotorasib and adagrasib tolerance.
In conclusion, the results of these two preclinical studies in cell models and PDOX represent an important step towards more precise and effective treatments against lung cancer. Once it advances into the clinical phase, it could open the door to new therapeutic combinations that could improve the prospects of many patients suffering from this disease.
The Bellvitge Biomedical Research Institute (IDIBELL) is a biomedical research center created in 2004. It is participated by the Bellvitge University Hospital and the Viladecans Hospital of the Catalan Institute of Health, the Catalan Institute of Oncology, the University of Barcelona and the City Council of L’Hospitalet de Llobregat.
IDIBELL is a member of the Campus of International Excellence of the University of Barcelona HUBc and is part of the CERCA institution of the Generalitat de Catalunya. In 2009 it became one of the first five Spanish research centers accredited as a health research institute by the Carlos III Health Institute. In addition, it is part of the “HR Excellence in Research” program of the European Union and is a member of EATRIS and REGIC. Since 2018, IDIBELL has been an Accredited Center of the AECC Scientific Foundation (FCAECC).