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Overcoming acquired BRAF inhibitor resistance in melanoma via targeted inhibition of Hsp90 with ganetespib.
Mol Cancer Ther. 2014 Feb; 13(2):353-63.MC

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.

Authors+Show Affiliations

Corresponding Author: David A. Proia, Synta Pharmaceuticals Corp, 125 Hartwell Avenue, Lexington, MA 02421. dproia@syntapharma.com.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

24398428

Citation

Acquaviva, Jaime, et al. "Overcoming Acquired BRAF Inhibitor Resistance in Melanoma Via Targeted Inhibition of Hsp90 With Ganetespib." Molecular Cancer Therapeutics, vol. 13, no. 2, 2014, pp. 353-63.
Acquaviva J, Smith DL, Jimenez JP, et al. Overcoming acquired BRAF inhibitor resistance in melanoma via targeted inhibition of Hsp90 with ganetespib. Mol Cancer Ther. 2014;13(2):353-63.
Acquaviva, J., Smith, D. L., Jimenez, J. P., Zhang, C., Sequeira, M., He, S., Sang, J., Bates, R. C., & Proia, D. A. (2014). Overcoming acquired BRAF inhibitor resistance in melanoma via targeted inhibition of Hsp90 with ganetespib. Molecular Cancer Therapeutics, 13(2), 353-63. https://doi.org/10.1158/1535-7163.MCT-13-0481
Acquaviva J, et al. Overcoming Acquired BRAF Inhibitor Resistance in Melanoma Via Targeted Inhibition of Hsp90 With Ganetespib. Mol Cancer Ther. 2014;13(2):353-63. PubMed PMID: 24398428.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Overcoming acquired BRAF inhibitor resistance in melanoma via targeted inhibition of Hsp90 with ganetespib. AU - Acquaviva,Jaime, AU - Smith,Donald L, AU - Jimenez,John-Paul, AU - Zhang,Chaohua, AU - Sequeira,Manuel, AU - He,Suqin, AU - Sang,Jim, AU - Bates,Richard C, AU - Proia,David A, Y1 - 2014/01/07/ PY - 2014/1/9/entrez PY - 2014/1/9/pubmed PY - 2015/2/20/medline SP - 353 EP - 63 JF - Molecular cancer therapeutics JO - Mol. Cancer Ther. VL - 13 IS - 2 N2 - 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. SN - 1538-8514 UR - https://www.unboundmedicine.com/medline/citation/24398428/Overcoming_acquired_BRAF_inhibitor_resistance_in_melanoma_via_targeted_inhibition_of_Hsp90_with_ganetespib_ L2 - http://mct.aacrjournals.org/cgi/pmidlookup?view=long&pmid=24398428 DB - PRIME DP - Unbound Medicine ER -