TAMPA, Fla. -- Researchers at Moffitt Cancer Center in Tampa, Fla., and colleagues in California have found that the XL888 inhibitor can prevent resistance to the chemotherapy drug vemurafenib, commonly used for treating patients with melanoma.
Vemurafenib resistance is characterized by a diminished apoptosis (programmed cancer cell death) response. According to the researchers, the balance between apoptosis and cell survival is regulated by a family of proteins. The survival of melanoma cells is controlled, in part, by an anti-apoptotic protein (Mcl-1) that is regulated by a particular kind of inhibitor.
Their current findings, tested in six different models of vemurafenib resistance and in both test tube studies and in melanoma patients, demonstrated an induced apoptosis response and tumor regression when the XL888 inhibitor restored the effectiveness of vemurafenib.
The study appeared in a recent issue of Clinical Cancer Research, a publication of the American Association for Cancer Research.
"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," said study co-author Keiran S. M. Smalley, Ph.D., of Moffitt's departments of Molecular Oncology and Cutaneous Oncology. "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 diversity of resistance mechanism has been expected to complicate the design of future clinical trials to prevent or treat resistance to inhibitors such as vemurafenib.
"That expectation led us to hypothesize that inhibitor resistance might best be managed through broadly targeted strategies that inhibit multiple pathways simultaneously," explained Smalley.
The HSP90 family was known to maintain cancer cells by regulating cancer cells,
|Contact: Ferdie De Vega|
H. Lee Moffitt Cancer Center & Research Institute