Suppressing a Specific Kinase Blocks Tumor Growth in Mouse Breast Cancer Model

A kinome screen was used to show that blocking the activity of a specific kinase inhibited the function of estrogen receptor-alpha (ER-alpha, encoded by ESR1), which is overexpressed in about two-thirds of breast tumors, and slowed growth of tumors in a mouse model of human breast cancer.

The kinome of an organism is the set of protein kinases in its genome. Kinases are enzymes that catalyze phosphorylation reactions (of amino acids) and fall into several groups and families, e.g., those that phosphorylate the amino acids serine and threonine, those that phosphorylate tyrosine and some that can phosphorylate both, such as the MAP2K and GSK families. As kinases are a major drug target and a major control point in cell behavior, the kinome has also been the target of large-scale functional genomics with RNAi screens and of drug discovery efforts, especially in cancer therapeutics.

In the current study published in the May 22, 2011, online edition of the journal Nature Medicine investigators at Imperial College London (United Kingdom) used RNAi screening techniques to show that lemur tyrosine kinase-3 (LMTK3) was among the most potent regulators of ER-alpha. Women who had higher levels of LMTK3 in their tumors tended to live less long and were less likely to respond to hormone therapy.

In a breast cancer mouse-model silencing of the LMTK3 gene with specific RNAi reduced tumor volume and abrogated proliferation of ER-alpha-positive but not ER-alpha-negative cells. LMTK3 acted by decreasing the activity of protein kinase C (PKC) and the phosphorylation of AKT (protein kinase B), thereby increasing binding of forkhead box O3 (FOXO3) to the ESR1 promoter. In addition, LMTK3 phosphorylated ER-alpha, protecting it from proteasomal degradation in vitro. This protection allowed unhindered expression of ER-alpha, which drove tumor formation.

"Anti-estrogen drugs have been very successful at allowing women with breast cancer to live longer, but resistance to these drugs is a common problem," said senior author Dr. Justin Stebbing, professor of surgery and cancer at Imperial College London. "Our results suggest that the action of LMTK3 on the estrogen receptor has a crucial role in the development of drug resistance. We are now looking for drugs that can block the effect of LMTK3, which we could hopefully give to patients to prevent them from becoming resistant to hormone therapy. It will probably take at least five to 10 years to develop new treatments that are safe to be used in humans."

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Imperial College London