IGR; France: 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 (www.nature.com/nature).
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.