French investigators have discovered new resistance mechanisms to targeted therapies used for less than three years in the treatment of melanoma. This discovery enables us not only to better understand why these treatments become ineffective but also to reveal new avenues for the management of these aggressive tumours. These studies have been published in the review Nature and have the benefit of an early on-line publication.
The treatment of metastatic melanoma remains a major problem in oncology. Half of the patients suffering from this disorder have a mutation of a protein called BRAF. Medicines targeting this mutated protein, vemurafenib (Zelboraf®) and dabrafenib (Tafinlar), enable the progression of this type of skin cancer to be significantly delayed. Unfortunately, over time, these anti-BRAF compounds loose their efficacy.
Investigators from the Predictive Biomarkers and new molecular strategies in anti-cancer therapy laboratory (Inserm/Gustave Roussy/Paris-Sud University) have shown that the mechanisms used by tumours to resist these treatments involves a protein complex called eIF4F which regulates the synthesis of proteins from RNA.
From the biopsies of tumours from patients, investigators also showed that the formation of this complex was diminished in tumours which responded to anti-BRAF and was increased in resistant metastases.
They have also shown that compounds developed by a pharmacochemistry team of the CNRS and by the University of Strasbourg which inhibit the elF4F complex bring about an improvement in the efficacy of vemurafenib in cellular and murine models.
These results offer new prospects for the prediction of the efficacy of melanoma treatments using medicines targeting the BRAF protein.
Moreover, over the long term they may result in more effective new treatments emerging to treat not only this fearsome type of cancer, but also certain types of thyroid, colon, lung and brain cancers.
These studies have been conducted by Stéphan Vagner (Inserm U981/Gustave Roussy/Université Paris-Sud, Villejuif; Current address: CNRS UMR3348/Institut Curie, Orsay) and by Caroline Robert (Inserm U981/Gustave Roussy, Dermatology Department/Paris-Sud University, Villejuif) in collaboration with Laurent Désaubry (Therapeutic Innovation Laboratory, CNRS UMR 7200/University of Strasbourg, Illkirch).
The team of Drs Caroline Robert and Stéphan Vagner was supported by PAIR melanoma (Fondation ARC, The league Against Cancer and by INCa), Cancéropôle Ile de France and the group “Ensemble contre le mélanome” (Together against Cancer). This study has also benefited from the support of AAREC Filia Research, from the Wenner-Gren Foundation and from the Swedish Society of Medicine.
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