Investigation of the molecular mechanism of GCK-inhibition as therapeutic approach in multiple myeloma

Description

In over half of multiple myeloma patients, RAS mutation is prevalent, presenting a currently undruggable target. Previous research conducted by the Lentzsch Lab revealed an upregulation of germinal center kinase (GCK) associated with RAS mutations, offering a new therapeutic approach (Li et al., Blood, 2021). Inhibition of GCK, achieved through either knockout or drug intervention, demonstrated a reduction in myeloma proliferation in RAS-mutated myeloma, both in vitro and in vivo. GCK plays a role in diverse pathways, including the proteasomal degradation of transcription factors IKZF1/3, distinct from the E3 ligase cereblon-dependent pathway crucial for the mode of action of immunomodulatory drugs (IMiDs). In our IMS-funded project, we aim to elucidate the pathway responsible for this degradation and identify the relevant E3 ligase complex. Additionally, we are assessing the role of IKZF1 degradation on the cytotoxic effects of GCK inhibition.