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New druggable vulnerabillty of colorectal cancer discovered

Colorectal cancer is the second most common tumor disease among women and the third most common among men in Germany. Intestinal tumors often form dangerous metastases in other organs. A team of researchers led by scientists at the National Center for Tumor Diseases (NCT) in Dresden and Heidelberg and the German Cancer Research Center (DKFZ), including scientists from the German Cancer Consortium (DKTK), has now discovered a new molecular target against particularly aggressive molecular subtypes of colorectal cancer: Knock out of a protein complex called cyclin K/CDK12 decreased proliferation of cancer cells in three-dimensional patient-derived cell culture systems. At the same time, the scientists succeeded in characterizing a previously unknown substance from the novel group of molecular glues. The research results obtained in cooperation with Bayer form the basis for the development of clinically applicable active substances for the degradation of cyclin K/CDK12. The National Center for Tumor Diseases Dresden (NCT/UCC) is a joint institution of the German Cancer Research Center (DKFZ), the University Hospital Carl Gustav Carus Dresden, Carl Gustav Carus Faculty of Medicine at TU Dresden and the Helmholtz-Zentrum Dresden-Rossendorf (HZDR).

In the laboratory, scientists investigate the efficacy of various substances on 3D cell cultures. © NCT/UCC/André Wirsig

A good 58,000 people in Germany are diagnosed with colorectal cancer every year. New therapies are urgently needed, especially for advanced colorectal cancers with non-operable metastases. A research team led by scientists at the National Center for Tumor Diseases (NCT) in Dresden and Heidelberg and the German Cancer Research Center (DKFZ) has now identified a structure, the protein complex cyclin K/CDK12, at which the tumor cells of particularly aggressive molecular subtypes of colorectal cancer can be very specifically targeted.

"This is an important basis for developing new drugs for patients with colorectal cancer in the future or for testing existing CDK12 inhibitors for their efficacy against these tumors," says Prof. Hanno Glimm, one of the managing directors at the National Center for Tumor Diseases Dresden (NCT/UCC), who additionally to his group here heads a research group at DKFZ in Heidelberg.

In their search for new approaches to colorectal cancer therapy, the scientists grew three-dimensional patient-derived cell culture systems in the laboratory that represent the structure and interaction of different cells in human intestinal tumors particularly well. The 24 different 3D cell cultures (spheroids) represented important genetic subtypes of colorectal cancer. The scientists used these models to test the effect of 80,000 substances. In the course of the compound screen, one substance proved to be particularly effective in triggering the degradation of cyclin K and CDK12.

The protein CDK12 has recently come into the focus of research as a possible target for various tumor types. For colorectal cancer, this link has not been explored so far. In association with cyclin K, CDK12 regulates important DNA repair mechanisms in cancer cells. If the cyclin K/CDK12 complex is increasingly degraded, this can lead to cells accumulating DNA damage and dying.

In the present colorectal cancer study, inactivation of cyclin K/CDK12 was particularly effective in some of the 3D cell models. These exhibited genetic alterations associated with a particularly poor prognosis and high probability of metastasis (molecular subtype 4). Further cell experiments showed that cyclin K/CDK12 can be targeted very specifically without affecting other proteins, whose inhibition can lead to serious side effects. "This very specific targeting possibility is highly relevant to us. It increases the chance that clinically applicable substances that trigger the degradation of cyclin K and CDK12 could in future be highly effective and well tolerated in a clearly defined group of patients with a particularly poor prognosis," explains Prof. Glimm. Further experiments also indicate that inhibition of CDK12 is also effective against tumor growth in combination with chemotherapeutic agents commonly used in colorectal cancer therapy.

The researchers also found that the previously uncharacterized substance for cyclin K/CDK12 inactivation that was successful in the cell experiment is an active ingredient from the novel substance class of molecular glues. Molecular glues attack cancer cells by an innovative mechanism: Unlike existing drugs, they do not directly inhibit cancer-driving structures or their activity, but feed them into the cell's own protein degradation machinery for disposal. For this purpose, they present the harmful target protein to an enzyme complex that marks the target protein and thus triggers its degradation. In the present case, cyclin K is labeled and degraded by the new substance, which subsequently also leads to the degradation of its complex partner CDK12.

So far, only a few representatives from the group of molecular adhesives are known. "The newly discovered molecular glue is further evidence of the high effectiveness of this new class of substances. Its effect in cell experiments shows how important further research into molecular glues is. In the future, they will make it possible to address molecular target structures that cannot be attacked with existing drugs," says first author Dr. Sebastian Dieter. In the future, the scientists want to modify the newly discovered molecular glue, if possible, so that it can be used as a clinically applicable active substance. Alternatively, similar substances with the same mechanism of action are to be researched.

Original Publication: S. M. Dieter, C. Siegl, P. L. Codó, et al. Degradation of CCNK/CDK12 is a druggable vulnerability of colorectal cancer. In: Cell reports, Volume 36, Issue 3, 20 July 2021; https://doi.org/10.1016/j.celrep.2021.109394