CeMM: A catalog of the human kinome in response to genotoxic stress, induced by chemotherapeutic agents

An important group of genes that is frequently mutated in cancer consists of kinases, which mediate communication within cells. As enzymes, kinases are promising candidates to target for cancer therapy and as such, by identifying interactions between kinases and chemotherapeutic drugs the treatment for cancer could be improved. A research team, led by CeMM PI Joanna Loizou, together with colleagues from the Francis Crick Institute and King´s College, London has now established a catalog of the human kinome in response to different types of genotoxic stress.

Chemotherapy is one of the standard treatments for cancer, and one of the main challenges in cancer treatment is to find means of causing maximum damage to cancer cells with minimum damage to normal cells, by identifying specific cancer vulnerabilities. A group of proteins known to play an important role in the DNA damage response is kinases. Indeed, many kinases are mutated in a variety of human cancers. However, when taken as a whole, it is apparent that the large majority of kinases are understudied. In their recent study, first author Michel Owusu, former PhD Student in Joanna Loizou´s group, and his colleagues, focused on inactivating mutations in kinases generated by CRISPR-Cas9.

By inactivating all possible kinases in human cells and treating them with different types of DNA damaging chemotherapeutic drugs they uncovered vulnerabilities to certain types of DNA damage. This is particularly important for genes such as MARK3 or EPHB6, which are less characterized and yet commonly inactivated in the development of cancer.

In addition, the researchers characterized the effect of selected chemotherapeutic drugs on cancer cells in regards to growth, death, cell cycle and DNA damage. They revealed that within cells, MARK3 mediated communication after DNA damage. In the absence of MARK3, this communication was disrupted, leading to increased death of cancer cells after treatment with DNA damaging chemotherapeutic drugs. Thus, MARK3 is a potential novel biomarker in the treatment of cancer.

The study “Mapping the human kinome in response to DNA damage” was published online in Cell Reports, on 15 January 2019, DOI: doi.org/10.1016/j.celrep.2018.12.087

Authors: Michel Owusu, Peter Bannauer, Joana Ferreira da Silva, Thanos P. Mourikis, Alistair Jones, Peter Májek, Michael Caldera, Marc Wiedner, Charles-Hugues Lardeau, André C. Mueller, Jörg Menche, Stefan Kubicek, Francesca D. Ciccarelli and Joanna I. Loizou

Funding: The study was funded by the Austrian Federal Ministry of Science, Research and Economy, the National Foundation for Research, Technology, and Development and Austrian Science Fund (FWF).