In this issue of Blood, Yao et al1 have elegantly proven that cyclin-dependent kinase-7 (CDK7) influences the oncogenic programming of multiple myeloma (MM) cells by modulation of MYC and E2F transcription factors. The authors show that CDK7 inhibition counteracts E2F activity, leading to a reduction of the CDKs-retinoblastoma (Rb) axis and inhibition of MYC-regulated metabolic signatures. Thus, CDK7 inhibition is an appealing therapeutic target for MM.
E2F deregulation is a hallmark of MM and is associated with aggressive forms of the disease.2 CDK7 inhibition activates Rb, thereby impacting E2F activity. However, cellular models of Rb inactivation, as well as genome-wide CRISPR knockout studies, suggest that CDK7 inhibition also works in the context of Rb loss and may effectively circumvent compensatory mechanisms by other cell cycle–associated kinases, as observed for the clinically available CDK4/6 inhibitors. Thus, CDK7 inhibition may have several therapeutic advantages. Therapeutic use of CDK inhibitors, including those targeting cyclin D partners CDK4/6, has been thwarted by the lack of single agent efficacy, suggesting that targeting of cell cycle regulation alone is insufficient to produce a durable response in MM.3 MM also relies on glycolysis for energy, and this increased dependence on glycolysis is due to MYC deregulation.4,5 This elicits a unique vulnerability separable from the lineage/enhancer axis targeted by immunomodulatory drugs and bromodomain and extra terminal protein inhibitors, which can be targeted by CDK7 inhibition. The current studies provide evidence for demonstrating how CDK7 controls MYC cellular levels in MM cells and that both translational and posttranslational regulatory mechanism may contribute to CDK7 regulation of MYC in MM cells.
Metabolic reprogramming is a hallmark of cancer.6 Tumor cells rely on aerobic glycolysis to supply energy by converting a majority of the glucose-derived pyruvate to lactate. Moreover, malignant cells engage glutamine anaplerosis to replace tricarboxylic acid cycle intermediates (eg, α-ketoglutarate), thus sustaining their metabolic status. Therefore, many human cancers use glucose and glutamine to rewire metabolism and to generate energy and sustain their growth. In contrast, normal cells have lower nutrient demands. Metabolic reprogramming represents a specific tumor cell vulnerability that could be therapeutically exploited.
In MM, metabolic signatures correlate with prognosis in MM.7 Lactate dehydrogenase (LDH) is one of the prognostic factors that predicts for adverse outcomes in MM patients. Hexokinase II and LDH A are found in newly diagnosed myeloma patients, and their expression has greater upregulation in relapsed MM cases, highlighting that the elevated glucose metabolism plays a more important role in relapsed compared with newly diagnosed MM.
The current study builds on recent literature suggesting that cell cycle progression is closely coupled to the cellular metabolism in tumor cells, with cell cycle regulators controlling glucose consumption and glycolysis. Does CDK7 have more global effects on metabolism beyond glycolysis? This question will have to be explored with further investigation.
Overall, the studies by Yao et al provide clear evidence that CDK7 inhibition is a promising therapeutic strategy for both newly diagnosed and relapsed MM disease, which should spare normal cells. Additional studies are needed to understand the impact of CDK7 inhibition on the immune microenvironment and how such inhibition will impact and interact with current immunotherapies in MM.
Conflict-of-interest disclosure: A.M.R. receives research funding from AstraZeneca, European Hematology Association, Transcan2ERANET, and Italian Association for Cancer Research (Fondazione AIRC) and honoraria from Amgen, Celgene, Janssen, and Takeda. A.S. declares no competing financial interests.