RICTOR amplification defines a novel subset of lung cancer patients who may benefit from treatment with mTOR1/2 inhibitors
A partir d'un échantillon tumoral prélevé sur un patient atteint d'un adénocarcinome du poumon (âge : 18 ans, non fumeur), puis menée sur des données génomiques portant sur deux cohortes indépendantes (2 086 patients au total) ainsi que in vitro et in vivo, cette étude identifie des mécanismes par lesquels une ampification du gène RICTOR favorise la croissance tumorale, et suggère l'intérêt d'un traitement à base d'inhibiteurs de mTOR1/2 pour les patients dont les tumeurs présentent cette anomalie génomique
We identified amplification of RICTOR, a key component of the mTORC2, as the sole actionable genomic alteration in an 18-year-old never smoker with lung adenocarcinoma. It occurs in 13% of lung cancers (1016 cases) in TCGA and at a similar frequency in an independent cohort of 1,070 patients identified by genomic profiling. In the latter series, 11% of cases harbored RICTOR amplification as the only relevant genomic alteration. Its oncogenic roles were suggested by decreased lung cancer cell growth both in vitro and in vivo with RICTOR ablation, and the transforming capacity of RICTOR in a Ba/F3-cell system. The mTOR1/2 inhibitors were significantly more active against RICTOR-amplified lung cancer cells as compared to other agents targeting the PI3K/AKT/mTOR pathway. Moreover, an association between RICTOR amplification and sensitivities to mTOR1/2 inhibitors was observed. The index patient has been treated with mTOR1/2 inhibitors that led to tumor stabilization for over 18 months.
SIGNIFICANCE: RICTOR amplification may define a novel and unique molecular subset of lung cancer patients who may benefit from treatment with mTOR1/2 inhibitors.
Cancer Discovery , résumé, 2015