Scientific research news

Novel immunotherapy with the CDK7 Inhibition Gives New Hope to Small Lung Cancer

pubdate:2020/02/25 source:

As a master regulator of cell cycle progression, cyclin-dependent kinase 7 (CDK7) functions as the catalytic core of CDK-activating kinase (CAK) complex. It is activated upon binding to Cyclin H and Mat1. This trimeric CAK complex activates several CDKs via the phosphorylation, ensuring progression in the cell cycle. Professor Gray’s lab recently reported the novel CDK7 inhibitor, YKL-5-124, potent anti-tumor immunity in small cell lung cancer (SCLC) with the hope of progression towards clinical trial and as new cancer immunotherapy (Figure 1).



Figure 1: Graphical abstract demonstrating the mechanisms elicited by CDK7 inhibitor, YKL-5-124 in eliciting genomic instability and anti-tumor immunity. (Figure is adopted from the journal article).


YKL-5-124 specifically bound to CDK7 with off-target of CDK12/13. Besides, YKL-5-124 inhibited the CDK1 and CDK2 T-loop phosphorylation. However, YKL-5-124 had no effect on the C-terminal domain (CTD) phosphorylation of RNA Pol ll, suggesting that selective CDK7 inhibition did not inhibit global transcription. These illustrated that YKL-5-124 specifically targeted CDK7. Furthermore, the YKL-5-124 potentiated the cytostatic effects on SCLC cells and implicated cytotoxic effect in longer time points. Besides, cell cycle analysis revealed a G1 phase arrest in SCLC cells upon YKL-5-124 treatment. Besides, the inhibition of CDK7 caused the genome instability an increased in the micronuclei formation. Subsequently, this directed the activation of DNA damage response. Furthermore, YKL-5-124 elicited anti-tumor immunity via the upregulation of pro-inflammatory pathways such as IFNγ and TNFα signalling pathways. These upregulated signalling pathways triggered the release of a vast amount of pro-inflammatory cytokines and chemokines, thus activating the cytotoxic CD8+ T cells.


The initiation of anti-tumor immunity by YKL-5-124 raised up the idea of combination therapy with immune checkpoint inhibitor anti-PD-1. The combination therapy had enhanced the overall survival of tumour-bearing mice. In tumour microenvironment, the mice underwent the treatment had increased CD44 high and CD62L low effector CD4 T cells with high proliferative Ki67 marker. The combination therapy also increased the release of granzyme B by CD8 cytotoxic T cells, led to increased cytotoxic activities in tumor cells. Furthermore, an increase of tumour resident CD11c, CD103 dendritic cells was observed. This assisted CD4 T cells to relay the signal for the activation of CD8 T cells cytolytic activities.  


In-depth characterization of the subpopulation of immune cells showed that the combination treatment of YKL-5-124 and anti-PD-1 elevated the natural killer cells and innate lymphoid cells besides T cells. Interestingly, the research team observed that a reduction in the CD4 and CD8 naïve T cells but a dramatic expansion of CD4 and CD8 effector/ memory T cells with upregulation of T cell activation gene signatures, signifying the robust and enhanced anti-tumor immunity.


 In summary, the inhibition of CDK7 triggered the strongest the anti-tumor immunity with the co-administration of anti-PD-1 via the modulation of the tumor-immune ecosystem such as elevating the anti-tumoral immune cells. With the further confirmation of clinical trial results, this combination therapy could be a new approach for cancer immunotherapy in treating SCLC patients in future.


The research was published in the Cancer Cell under Cell Press which can be found in



Zhang H, Christensen CL, Dries R et al. (2020) CDK7 inhibition potentiates genome instability triggering anti-tumor immunity in small cell lung cancer. Cancer Cell. 37: 37-54.