Posted: Wednesday, July 31, 2024
According to Kate Vandyke, PhD, of the University of Adelaide, Australia, and colleagues, elevated expression of the G protein–coupled receptor C-C motif chemokine receptor 1 (CCR1) may be associated with a decreased response to proteasome inhibition with bortezomib, and thus a poor prognosis, in newly diagnosed patients with multiple myeloma. Their preclinical findings, which were published in the journal Leukemia Research, implicate a mechanism involving decreased expression of the unfolded protein response transmembrane stress sensor inositol-requiring kinase 1 (IRE1) in this phenomenon.
The investigators induced CCR1 overexpression in the murine cell line 5TGM1 and CRIPSR-Cas9–mediated CCR1 knockout in the human cell lines OPM2 and U266. Mice of the NOD/SCID-gamma strain were inoculated intratibially with OPM2 CCR1 knockout cells and treated with either 0.7 mg/kg of bortezomib or a vehicle twice weekly for 3 weeks. Using these models, the investigators conducted several laboratory assessments.
The expression of CCR1 was found to significantly decrease sensitivity to bortezomib in vitro; neither the CCR1 ligand C-C motif chemokine ligand 3 (CCL3) of exogenous nor endogenous origin appeared to modulate this response. Additionally, in the NOD/SCID-gamma murine model, CCR1 knockout reportedly rendered the OPM2 cell line more sensitive to bortezomib therapy. The expression of CCR1 was found to negatively regulate the expression of both IRE1 and the downstream target gene XBP1; according to the investigators, this pathway could be responsible for the decreased sensitivity of CCR1-expressing cells to bortezomib.
“These results are of potential importance, as bortezomib and the related proteasome inhibitors carfilzomib and ixazomib are commonly used in multiple myeloma therapeutic regimens,” the investigators concluded. “Future studies are warranted to examine whether CCR1 may be a useful biomarker to predict the response to bortezomib therapy and whether CCR1 inhibition can resensitize resistant multiple myeloma cells to bortezomib therapy.”
Disclosure: The study authors reported no conflicts of interest.
