“TRIMing” the Patient Population to Increase the Benefit of mTOR Inhibition
A partir de données génomiques et transcriptomiques portant sur 1 932 cancers épithéliaux, 1 980 cancers du sein et 163 cancers œso-gastriques, puis à l'aide de lignées cellulaires et de xénogreffes, cette étude suggère l'intérêt de l'évérolimus, un inhibiteur de mTOR, pour le traitement des tumeurs surexprimant TRIM44
Targeted therapies for cancer hold great promise because of their specificity for characteristics unique to cancer cells. However, often only a small proportion of cancers are susceptible to a particular targeted therapy. Optimal patient selection requires a biomarker to predict drug sensitivity such that selected individuals have a high likelihood of benefit. The era of targeted therapies has spawned several successful biomarker–drug pairs, such as HER2 amplification and trastuzumab (1), EGFR mutation and erlotinib (2), and B-raf and vemurafenib (3). The selection of a potentially active agent is obvious when it directly reverses the activity of an oncogene, which is activated through amplification or mutation.
Anomalies in this general paradigm for targeted drug–biomarker pairs have emerged. Some highly targeted drugs downregulate oncogenic signaling pathways by inactivating proteins that are not directly activated by amplification or mutation. Foremost among these is rapamycin, a targeted inhibitor of mTOR and its analogs everolimus and temsirolimus. mTOR is often thought to be a central mediator of growth signaling through PIK3CA mutations in many cancers (4). In spite of having these drugs that specifically target mTOR, no standard predictive biomarker exists to identify patients likely to benefit. Simply assaying upstream activation of mTOR as an approach to patient selection …
Journal of the National Cancer Institute , éditorial, 2014