Abstract
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 BRAF(V600E) 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 BRAF(V600E) mutation. Ganetespib exposure resulted in the loss of mutant BRAF expression and depletion of mitogen-activated protein kinase and AKT signaling, resulting in greater in vitro potency and antitumor efficacy compared with targeted BRAF and MAP-ERK kinase (MEK) inhibitors. Dual targeting of Hsp90 and BRAF(V600E) 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 extracellular signal-regulated kinase (ERK) signaling. Continued suppression of BRAF(V600E) 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 BRAF(V600E)-driven melanoma, particularly as a strategy to overcome acquired resistance to selective BRAF inhibitors.
Highlights
Cutaneous melanoma ranks among the most aggressive and treatment-resistant human malignancies [1], and at a time when the overall incidence and mortality rates for many cancer types are showing encouraging declines [2], the worldwide incidence of melanoma continues to increase [3]
Ganetespib treatment resulted in a robust and dose-dependent decrease in levels of both BRAF and CRAF; this was accompanied by inactivation of downstream mitogen-activated protein kinase (MAPK) signaling, as evidenced by loss of the phosphorylated effectors p-MAP–extracellular signal-regulated kinase (ERK) kinase (MEK) and p-ERK (Fig. 1B)
Hsp90 inhibition resulted in the selective destabilization of mutated BRAF as shown for SK-MEL-28 cells, in contrast with the wild-type form of the protein expressed in normal melanocytes and the SKMEL-2 melanoma line (Fig. 1C)
Summary
Cutaneous melanoma ranks among the most aggressive and treatment-resistant human malignancies [1], and at a time when the overall incidence and mortality rates for many cancer types are showing encouraging declines [2], the worldwide incidence of melanoma continues to increase [3]. Mutational activation of the serine-threonine kinase BRAF, resulting in dysregulation of the RAF/MEK/ERK mitogen-activated protein kinase (MAPK) signaling cascade, is a feature of over. Authors' Affiliation: Synta Pharmaceuticals Corp., Lexington, Massachusetts. Note: Supplementary data for this article are available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org/). J. Acquaviva and D.L. Smith contributed to the work.
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