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CDK6 in transcription - turning a foe in a friend

Periodic Reporting for period 4 - CDK6-DrugOpp (CDK6 in transcription - turning a foe in a friend)

Reporting period: 2021-03-01 to 2022-08-31

Although we have made significant progress in cancer research and in the development of novel diagnostic and therapeutic strategies, many cancer types remain an unresolved issue. Among the tumor types lacking adequate therapeutic strategies are certain forms of blood cancer. Many of these upregulate a certain molecule called cyclin-dependent kinase 6 (CDK6). We have shown that CDK6 not only exerts its proposed function to regulate cell proliferation by governing the cells through the cell cycle but also regulates the transcription of genes important for tumor formation explaining the selective pressure of up-regulating this molecule. In this project we aimed to identify the interactors of CDK6 which are crucial for regulating transcription and thereby different pathways which are essential for a leukemic cell. These data are crucial to define novel therapeutic strategies. During the course of the project we have been able to describe interactors of CDK6, some of which critically interfere with the function of currently available CDK6 inhibitors. This may now be used to stratify which patients may benefit from conventional CDK6 kinase inhibitors.
To overcome the limitations of studying the specific roles of CDK6 in untransformed and transformed stem/progenitor cells we established a novel stem/progenitor cell system which is already widely used in the scientific community. These cell lines are immortal and proliferate endlessly in culture while keeping their stem/progenitor cell features. This allowed us to define common and specific pathways regulated by CDK6 in an untransformed and transformed stem/progenitor cell setting. These studies are of great relevance as leukemia is driven by a rare leukemic stem cell population which is hard to target. We further exploited the novel cellular system and defined regions within the CDK6 molecule important for functions that drive leukemia. This knowledge will enable us to work on novel therapeutic strategies to target CDK6. We are also currently developing an innovative mouse model for CDK6 that will further help us to understand under which conditions CDK6 is critical in tumor progression and how it is regulated. To define the vulnerable nodes driving cancer will open novel avenues for drug development.
The ERC grant enabled us to understand how CDK6 regulates gene transcription of distinct genes to drive leukemia. It also enabled us to understand how CDK6 interferes with p53, an important check point in cancer and considered the gate keeper of the genome. CDK6 not only allows for cell proliferation but also antagonizes p53-induced cell death when a cell evolves into a tumor cell. P53 triggers cellular suicide when a cell enters the state of transformation, a function blocked by high CDK6 levels. Thereby, CDK6 is required to allow the birth of leukemic cells (Bellutti et al 2018). In this publication we could unravel the underlying molecular mechanisms for this novel function of CDK6.
Cancer cells require a distinct metabolic state. Also in this area CDK6 contributes to changes in the mitochondrial pathway, a project that is still ongoing. To target the metabolism of a tumor cell is currently considered key to treat cancer and our findings will help to finally understand the switches in metabolism of a tumor cell.
Leukemic stem cells are hard to target and studies on this small population of cells difficult. WE thus generated a novel cellular tool and found a way how to maintain the small population of hematopoietic stem cells (HSCs) and their leukemic counterparts (LSCs) in culture. Few stem cells suffice to generate the entire blood flowing through our body, which we now can keep in culture (Doma et al. 2021). These cell lines expressing various versions of CDK6 allowed us to unravel CDK6’s function in hematopoiesis and leukemogenesis. We found that CDK6 supports HSC dormancy as well as HSC repopulation with distinct functions – these distinct features being unraveled by the use of different mutations driving unique gene expression patterns. These results now help to understand how HSCs and their activation are regulated by CDK6 and may be further exploited in therapeutic settings.
This novel cell lines have also been used to generate different versions of leukemic stem cells that faithfully recapitulate human blood cancer in mice and represent a valuable novel tool. First studies are ongoing in the lab to understand the molecular mechanisms of cellular transformation and the role of CDK6 therein. A first publication shows that the expression of the INK proteins, CDK6 kinase inhibitors, dictate the responsiveness of the cells to current CDK6 targeting options in leukemia (Schmalzbauer et al. 2022).
Results have been presented at several conferences and seminars whenever possible. Publications are under progress and students will finish their PhD thesis. Numerous collaborations could be made thanks to new research areas which have been opened during the project.
The project helped to enter new grounds and unraveled unexpected new functions for CDK6 in tumor formation. These results open novel vulnerabilities for combinatorial treatments with CDK6 inhibitors. The insights gained in the project will shape the future for designing new targeting strategies of CDKs and help to define patient subsets that benefit from a CDK6 directed therapy.

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