Although HER2-positive breast cancer can be treated with the drug Herceptin, it typically develops resistance within several years. A multi-institutional team has found a means of inhibiting another protein, protein tyrosine phosphatase 1B (PTP1B), whose expression is also upregulated in HER2-positive breast cancer. PTP1B has a critical role in the development of tumors in which HER2 signaling is aberrant.
The breast cancer subtype in question is commonly called “HER2-positive”; it’s a subset of the disease affecting about one patient in four, in which tumor cells overexpress the HER2 signaling protein. Because resistance to the drug Herceptin develops within several years in most cases, the prognosis for patients with HER2-positive breast cancer is worse than for those with other subtypes of the disease.
Scientists at Cold Spring Harbor Laboratory (CSHL) in New York, led by Nicholas Tonks, PhD, and their collaborators hope their discovery will lead to the development of a powerful new way of treating an aggressive form of breast cancer. Their research was reported in Nature Chemical Biology (2014; doi:10.1038/nchembio.1528).
Tonks and colleagues found that treating mice modeling HER2-positive breast cancer with the PTP1B inhibitor MSI-1436 (also called trodusquemine), inhibited HER2 protein signaling.
“The result was an extensive inhibition of tumor growth and prevention of metastasis to the lung in HER2-positive animal models of breast cancer,” noted Navasona Krishnan, PhD, a postdoctoral investigator in the Tonks lab who performed many of the experiments and is lead author on the paper reporting the results.
Tonks discovered PTP1B some 25 years ago. It is an enzyme, among a “superfamily” of 105 called protein tyrosine phosphatases, that performs the essential biochemical task of removing phosphate groups from amino acids called tyrosines in other proteins. Adding and removing phosphate groups is one of the means by which signals are sent among proteins.
For many years, PTP1B has been a target of interest among drug developers. It is well known to be a negative regulator of insulin, or an antagonist of insulin signaling, and of signaling by leptin, the hormone that helps regulate appetite. Drugs that can block or inhibit the action of PTP1B have great potential in controlling diabetes and obesity. Yet properties of the molecule that involve both its charged active binding site and its shape have stymied potential developers of inhibitory drugs.
The new paper importantly reveals an alternative binding site (called an allosteric site) that does not present the biochemical difficulties that the active, or catalytic, binding site does. This allosteric site is a target of the candidate drug trodusquemine.
Later this year early stage human trials will begin for the drug, a collaboration of CSHL and North Shore-Long Island Jewish Hospital. Tonks and CSHL have interests in a joint venture called DepYmed Inc., in partnership with Ohr Pharmaceutical. The venture seeks to develop trodusquemine and related analogs.