Prof. Dr. Alexander Roesch

Clinic for Dermatology

University Hospital Essen

Phone: +49 201 723 4747
Email

Despite modern cancer therapies, most cases of metastatic melanoma remain fatal. Various studies provide insights into how melanoma cells adapt to therapy stress via reversible phenotypic transitions before becoming fully, i.e. genetically, resistant. However, these studies do not address the process of very early cell selection, when intrinsically resistant phenotypes (slow-cycling drug-tolerant persisters) survive drug exposure. Moreover, not much attention has been given to strategies that target the dynamics of this early phenotype selection. JARID1B/KDM5B is a histone demethylase that is a slow-cycling and melanoma resistance marker. Our previous work suggests that JARID1B^high slow-cycling persisters confer early therapy resistance and tumor repopulation. In this project, we are focusing on how the intrinsically drug resistant melanoma cell state highly expressed JARID1B is an integral controller of both differentiation and cell cycle arrest. Specifically, we will address the role of JARID1B on differentiation, and cell cycle of melanoma cells by acutely inhibiting JARID1B expression via PROteolysis-TArgeting Chimeras (PROTAC). Further, we will study the functions of the various JARID1B domains by generating cell lines expressing catalytically inactive mutants, and finally target JARID1B-dependent resistant states in vitro and in vivo.