2:43 PM
Mar 13, 2018
 |  BC Extra  |  Preclinical News

CDK6 a potential obesity target

A study published in Nature Communications suggests cyclin dependent kinase 6, a known molecular target for cancer, could also be targeted to treat obesity and metabolic diseases.

White adipose tissue (WAT) stores energy in rodents and humans, while brown adipose tissue (BAT) exudes thermal energy. Beige cells, which are brown adipocytes that develop in white adipose tissues in response to cold and other stimuli, are linked to reduced obesity in rodent models and humans.

Multiple researchers are attempting to identify targets that induce brown fat activity and beige fat differentiation to combat obesity and metabolic disorders (see BioCentury Innovations, March 10, 2016).

The researchers from Tufts Medical Center and colleagues first observed that CDK6 mRNA and protein levels of mice on a high-fat diet were up-regulated in WAT, but not in BAT. CDK6 protein levels were also higher in mice that had fasted overnight than mice on a normal diet, suggesting that CDK6 responds to changes in nutritional state.

The team then found that mice lacking the CDK6 kinase domain gained less weight and had improved blood glucose tolerance and insulin sensitivity compared with mice with normal CDK6 expression. The kinase domain knockout mice also had browner posterior subcutaneous and inguinal WAT and higher expression of BAT-specific genes in inguinal WAT, suggesting that loss of CDK6 kinase activity leads to increased beige cell production and white fat browning.

The CDK6 kinase domain knockout mice also had increased energy expenditure and body temperature than mice with normal CDK6 expression. The researchers suggested eliminating CDK6 kinase activity lowers weight in rodents via increased thermogenesis.

Eli Lilly and Co. (NYSE:LLY), Novartis AG (NYSE:NVS: SIX:NOVN) and Pfizer Inc. (NYSE:PFE) each market a dual inhibitor of CDK6 and CDK4 for cancer indications.

Lilly’s Verzenio abemaciclib is approved as monotherapy for hormone receptor-positive, HER2-negative advanced or metastatic breast cancer in previously treated patients and as a combination treatment in first-line or later settings. Novartis markets Kisqali ribociclib and Pfizer markets Ibrance palbociclib in combination with other agents to treat hormone receptor-positive, HER2-negative advanced or metastatic breast cancer. Each company is also evaluating its product in the clinic to treat other cancers.

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