Concurrent MEK2 Mutation and BRAF Amplification Confer Resistance to BRAF and MEK Inhibitors in Melanoma
Menée in vitro, cette étude suggère l'intérêt d'un traitement combinant dabrafenib, trametinib et un inhibiteur de PI3K/mTOR (GSK2126458) pour surmonter la résistance thérapeutique chez les patients atteints d'un mélanome métastatique présentant des mutations du gène MEK2 et une amplification du gène BRAF
Although BRAF and MEK inhibitors have proven clinical benefits in melanoma, most patients develop resistance. We report a de novo MEK2-Q60P mutation and BRAF gain in a melanoma from a patient who progressed on the MEK inhibitor trametinib and did not respond to the BRAF inhibitor dabrafenib. We also identified the same MEK2-Q60P mutation along with BRAF amplification in a xenograft tumor derived from a second melanoma patient resistant to the combination of dabrafenib and trametinib. Melanoma cells chronically exposed to trametinib acquired concurrent MEK2-Q60P mutation and BRAF-V600E amplification, which conferred resistance to MEK and BRAF inhibitors. The resistant cells had sustained MAPK activation and persistent phosphorylation of S6K. A triple combination of dabrafenib, trametinib, and the PI3K/mTOR inhibitor GSK2126458 led to sustained tumor growth inhibition. Hence, concurrent genetic events that sustain MAPK signaling can underlie resistance to both BRAF and MEK inhibitors, requiring novel therapeutic strategies to overcome it. "MEK2Q60P mutation and BRAF amplification confer resistance to BRAF and MEK inhibitors "ERK and S6K are persistently phosphorylated in the BRAF- and MEKi-resistant tumor cells "A triple combination of BRAF, MEK, and PI3K inhibitors overcomes resistance in vivo The therapeutic efficacy of MEK and BRAF inhibitors is limited by the emergence of drug resistance. Hence, it is critical to understand all mechanisms of resistance and develop strategies to overcome them. Here, Villanueva, Herlyn, and colleagues demonstrate that concurrent MEK2 mutations and BRAF amplification confer resistance to BRAF and MEK inhibitors in melanoma. The authors demonstrate that resistant melanoma cells had sustained S6K phosphorylation; a triple combination of BRAF, MEK, and PI3K/mTOR inhibitors caused sustained growth inhibition of resistant tumors.
http://linkinghub.elsevier.com/retrieve/pii/S2211124713004646