Combination therapy targeting Erk1/2 and CDK4/6i in relapsed refractory multiple myeloma.

Abstract

Oncogenic activated RAS mutations have been detected in 50% of de novo and 70% of relapsed multiple myeloma (MM) patients. Translocation t(11;14) involving IgH/CCDN1 and overexpression of cyclin-Ds are early events in MM pathogenesis, enhancing uncontrolled MM cell growth. We hypothesized that targeting both RAS/MAPK pathway molecules including Erk1/2 along with cyclin-Ds enhances MM cytotoxicity and minimizes side effects. Recent studies have demonstrated the high potency of Erk1/2 and CDK4/6 inhibitors in metastatic relapsed cancers, and here we tested anti-MM effects of the Erk1/2 + CDK4/6 inhibitor combination. Our studies showed strong synergistic (IC < 0.5) cytotoxicity of Erk1/2i + CDK4/6i in MM-cells. Erk1/2i + CDK4/6i treatment in a dose-dependent manner arrested MM-cells in the G0/G1 phase and activated mitochondrial apoptotic signaling. Our studies showed that Erk1/2i + CDK4/6i treatment-induced inhibition of key target molecules in Erk1/2 and CDK4/6 signaling, such as c-myc, p-RSK, p-S6, p-RB, and E2F1, suggesting on-target activity of these inhibitors. We identified Erk1/2i + CDK4/6i treatment associated five-gene signature which includes SNRPB and SLC25A5; these genes are involved in RNA processing and mitochondrial metabolism, respectively. Overall, our studies provide the preclinical framework for Erk1/2i + CDK4/6i combination clinical trials to target Ras+CDK pathways to improve patient outcome in MM.

• Authors: Sophia Adamia, Shruti Bhatt, Kenneth Wen, Zuzana Chyra, Geoffrey G Fell, Yu-Tzu Tai, Marisa S Pioso, Ivane Abiatari, Anthony Letai, David M Dorfman, Teru Hideshima, Kenneth C Anderson
• Journal: Leukemia (Leukemia) Vol. 36 Issue 4 Pg. 1088-1101 (04 2022) ISSN: 1476-5551 [Electronic] England
• PMID: 35082402 (Publication Type: Journal Article)
• Copyright: © 2021. The Author(s).

Chemical References

• Protein Kinase Inhibitors
• CDK4 protein, human
• Cyclin-Dependent Kinase 4
• Cyclin-Dependent Kinase 6

Topics

• Breast Neoplasms (drug therapy)
• Cyclin-Dependent Kinase 4
• Cyclin-Dependent Kinase 6
• Female
• Humans
• Multiple Myeloma (drug therapy)
• Neoplasm Recurrence, Local (drug therapy)
• Protein Kinase Inhibitors (therapeutic use)