Inhibitor thwarts vemurafenib resistance

Tampa, Fla. - Results of a new study indicate that the XL888 inhibitor can prevent resistance to vemurafenib (Zelboraf, Hoffman-La Roche), a drug widely used for treating melanoma patients.

Researchers at Moffitt Cancer Center, here, and colleagues in California found that vemurafenib resistance is characterized by a diminished apoptosis response and that the balance between apoptosis and cell survival is regulated by a family of proteins. The survival of melanoma cells is controlled, in part, by the anti-apoptotic protein Mcl-1, which is regulated by a particular kind of inhibitor.

The current findings, tested in six different models of vemurafenib resistance and in both test-tube studies and melanoma patients, demonstrate an induced apoptosis response and tumor regression when the XL888 inhibitor restored the effectiveness of vemurafenib.

In a statement issued by Moffitt Cancer Center, study co-author Kieran S.M. Smalley, Ph.D., says, “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. However, we have demonstrated for the first time that the heat shock protein-90 (HSP90) inhibitor XL888 overcomes resistance through a number of mechanisms.”

The HSP90 family was known to maintain cancer cells by regulating cancer cells, making it a good target for treatment. According to the authors, the combination of vemurafenib and XL888 overcame vemurafenib resistance by targeting HSP90 through multiple signaling pathways.

“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,” the researchers write. “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 study appears in the journal Clinical Cancer Research.

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