Experimental Drug Reverses Vemurafenib Resistance in Malignant Melanoma

The experimental drug XL888 was shown to block growth of melanoma cells that had become resistant to the BRAF inhibitor vemurafenib both in vitro and in a mouse xenograft model.

Vemurafenib only works in melanoma patients whose cancer has a V600E BRAF mutation (that is, at amino acid position number 600 on the B-Raf protein, the normal valine is replaced by glutamic acid). About 60% of melanomas have this mutation. Melanoma cells without this mutation are not inhibited by vemurafenib; the drug paradoxically stimulates normal BRAF and may promote tumor growth in such cases.

XL888 is an orally available small molecule inhibitor of HSP90 (heat shock protein 90), a chaperone protein that promotes the activity and stability of a range of client proteins, including kinases, which play key regulatory roles in cells. The activity of HSP90 is particularly prominent in tumor cells, where it promotes the activity of proteins controlling proliferation and survival. XL888 is a potent and selective ATP-competitive inhibitor of HSP90, and binds to its target in a manner that is structurally distinct from other HSP90 inhibitors currently in use.

Investigators at Moffitt Cancer Center (Tampa, FL, USA) recently demonstrated the potential therapeutic utility of XL888 in six different models of vemurafenib resistance. The ability of XL888 to inhibit growth and to induce apoptosis and tumor regression of vemurafenib-resistant melanoma cell lines was demonstrated in vitro and in vivo. A novel mass spectrometry-based pharmacodynamic assay was developed to measure intratumoral HSP70 levels following HSP90 inhibition in melanoma cell lines, xenografts, and melanoma biopsies.

Results published in the February 20, 2012, online edition of the journal Clinical Cancer Research revealed that XL888 potently inhibited cell growth, induced apoptosis, and prevented the growth of vemurafenib resistant melanoma cell lines in three-D cell culture, long-term colony formation assays, and human melanoma mouse xenografts.

"We have shown for the first time that all of the signaling proteins implicated in vemurafenib resistance are "clients" of HSP90 and that inhibition of HSP90 can restore sensitivity to vemurafenib," said senior author Dr. Keiran S. M. Smalley, professor of oncology at Moffitt Cancer Center. "Our study provides the rationale for the dual targeting of HSP90 with XL888 and vemurafenib in treating melanoma patients in order to limit or prevent chemotherapy resistance. The impressive clinical response of melanoma patients to vemurafenib has been limited by drug resistance, a considerable challenge for which no management strategies previously existed. That expectation led us to hypothesize that inhibitor resistance might best be managed through broadly targeted strategies that inhibit multiple pathways simultaneously."

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