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ERK1/2 and CDK4/6 Inhibitor Combination Under Study in Resistant Myeloma

By: Julia Fiederlein
Posted: Monday, July 11, 2022

Kenneth C. Anderson, MD, of Harvard Medical School, Boston, and colleagues conducted a study to investigate the anti–multiple myeloma effects of an ERK1/2 (LY3214996) and CDK4/6 (LY2835219) inhibitor combination. The results, which were published in the journal Leukemia, provide the preclinical framework for clinical trials to target the RAS and CDK pathways in patients with relapsed or refractory disease.

“Our studies demonstrate that ERK1/2 and CDK4/6 inhibitors inhibited multiple myeloma cell survival and induced mitochondrial-dependent apoptosis, associated with downregulation of key target molecules c-Myc, p-RSK, p-S6, p-RB, and E2F1 in multiple myeloma cell lines and patient cells with complex genetic profiles,” the investigators remarked. “Importantly, our studies showed synergistic anti–multiple myeloma activity of the ERK1/2 and CDK4/6 inhibitor combination in vitro and in vivo, as well as identified biomarkers associated with response to this treatment.”

To target RAS/CDK4/6-dependent pathways in multiple myeloma, the investigators examined the effects of ERK1/2, CDK4/6, and ERK1/2 plus CDK4/6 inhibition using in vitro and in vivo preclinical models. According to the investigators, the ERK1/2 and CDK4/6 inhibitor combination demonstrated strong synergistic cytotoxicity (combination index <  0.5) in multiple myeloma cells. Treatment with this combination in a dose-dependent manner arrested multiple myeloma cells in the G0/G1 phase and activated mitochondrial apoptotic signaling.

Inhibition of key target molecules in ERK1/2 and CDK4/6 signaling—such as c-Myc, p-RSK, p-S6, p-RB, and E2F1—was observed with the ERK1/2 and CDK4/6 inhibitor combination; this finding suggested on-target functional activity of these inhibitors. The investigators identified an ERK1/2 and CDK4/6 inhibitor treatment–associated five-gene signature, which included SNRPB and SLC25A5; these genes are involved in RNA processing and mitochondrial metabolism, respectively.

Disclosure: For full disclosures of the study authors, visit

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