Overcoming Acquired BRAF Inhibitor Resistance in Melanoma via Targeted Inhibition of Hsp90 with Ganetespib
Menée in vitro et in vivo, cette étude évalue l'activité antitumorale du ganetespib, un inhibiteur de la protéine de choc thermique Hsp90, pour surmonter une résistance au vémurafénib dans le traitement d'un mélanome présentant la mutation V600E du gène BRAF
Activating BRAF kinase mutations serve as oncogenic drivers in over half of all melanomas, a feature that has been exploited in the development of new molecularly-targeted approaches to treat this disease. Selective BRAFV600E inhibitors, such as vemurafenib, typically induce initial, profound tumor regressions within this group of patients; however durable responses have been hampered by the emergence of drug resistance. Here we examined the activity of ganetespib, a small molecule inhibitor of Hsp90, in melanoma lines harboring the BRAFV600E mutation. Ganetespib exposure resulted in the loss of mutant BRAF expression and depletion of MAPK and AKT signaling, resulting in greater in vitro potency and antitumor efficacy compared to targeted BRAF and MEK inhibitors. Dual targeting of Hsp90 and BRAFV600E provided combinatorial benefit in vemurafenib-sensitive melanoma cells in vitro and in vivo. Importantly, ganetespib overcame mechanisms of intrinsic and acquired resistance to vemurafenib, the latter of which was characterized by reactivation of ERK signaling. Continued suppression of BRAFV600E by vemurafenib potentiated sensitivity to MEK inhibitors after acquired resistance had been established. Ganetespib treatment reduced, but not abolished, elevations in steady-state ERK activity. Profiling studies revealed that the addition of a MEK inhibitor could completely abrogate ERK reactivation in the resistant phenotype, with ganetespib displaying superior combinatorial activity over vemurafenib. Moreover, ganetespib plus the MEK inhibitor TAK-733 induced tumor regressions in vemurafenib-resistant xenografts. Overall these data highlight the potential of ganetespib as a single-agent or combination treatment in BRAFV600E-driven melanoma, particularly as a strategy to overcome acquired resistance to selective BRAF inhibitors.
http://mct.aacrjournals.org/content/early/2014/01/07/1535-7163.MCT-13-0481.abstract