LMTK3: image adapted from the paper

An international study led by scientists at the University of Sussex has provided strong evidence for an effective new target for breast cancer treatment.

The roughly five-year study, which involved researchers from seven institutions across three countries, suggests that LMTK3 inhibitors could be effectively used for the treatment of breast cancer, and potentially other types of cancer.

LMTK3, a previously identified regulator of Estrogen receptor alpha, is a protein implicated in the development and progression of different malignancies and other diseases, including some related to the central nervous system, and it is not typically included in commercial kinase screening assays (a drug discovery technique).

Now, research successfully demonstrates that LMTK3 is an active kinase and reports a compound which binds to, and effectively inhibits, this protein, resulting in anticancer effects in cells and in breast cancer models in mice.

It is hoped the research will allow the further development and optimisation of LMTK3 inhibitors as a new type of orally-administered anticancer drug for patients.

Georgios Giamas, Professor of Cancer Cell Signalling, who led the research, said: “By solving the crystal structure of LMTK3, we have demonstrated that it possesses all of the hallmarks of an active protein kinase. LMTK3 plays a pivotal role in controlling cellular processes, and we have previously shown that active LMTK3 makes some cancer treatments (eg. chemotherapy and endocrine therapies) less effective.

“We are now in the process of taking this research to the next stage by developing LMTK3 specific drugs. We hope that in the next five years we will be undertaking clinical trials, which is incredibly quick for this type of process.”

Dr Angeliki Ditsiou, first author of the paper, added: "It is hard but also very exciting to work on a protein about which very little is known. We welcomed the challenge and we not only provided further information about LMTK3, we also identified and characterized the first LMTK3 inhibitor. The approach taken required the fine melding of several specialties (biochemistry, structural and molecular biology as well as medicinal chemistry) proving that interdisciplinary exploration is of crucial importance to any complex problem, including cancer."

The researchers hope that further development and optimisation of LMTK3 inhibitors on the basis of this study could have potential value not only for breast cancer patients but also for lung, stomach, thyroid and bladder cancer patients.

It is expected that the development of oral LMTK3 inhibitors may have the potential for broad clinical utility, either as a monotherapy, or as a combinational therapy, for example combined with chemotherapy, immunotherapy or endocrine treatments. Consequently, an LMTK3 inhibitor could be used alongside complementary therapies to increase the therapeutic efficacy and help overcome mechanisms of resistance to existing cancer therapies.

The structure-function relationship of oncogenic LMTK3 is published in the journal Science Advances.

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