Reactome | Drug-mediated inhibition of CDK4/CDK6 activity

Drug-mediated inhibition of CDK4/CDK6 activity

Stable Identifier

R-HSA-9754119

DOI

10.3180/R-HSA-9754119.1

Type

Pathway

Species

Homo sapiens

ReviewStatus

5/5

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Drug-mediated inhibition of CDK4/CDK6 activity

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Cyclin dependent kinases CDK4 and CDK6 regulate crucial steps in the G1 phase of the cell cycle that commit cells to transition to the S phase and ultimately divide. Many growth signaling pathways, frequently perturbed in cancer, converge on CDK4/CDK6 activation, thus driving cellular proliferation. This makes CDK4 and CDK6 promising targets for anti-cancer therapy. So far, three CDK4/6 inhibitors, palbociclib, ribociclib and abemaciclib, have been approved for clinical use and many others are at different stages of clinical testing. CDK4/6 inhibitors mainly have a cytostatic effect on tumor cells, but can also influence immune response to tumor by targeting immune system cells in the tumor microenvironment. While intact RB1, the main target of CDK4/6 during cell cycle progression, is in general considered to be a prerequisite for the success of CDK4/6-targeted anti-cancer therapy, the status of other, less explored CDK4/6 targets can also affect the treatment outcome. For review, please refer to Asghar et al. 2015, Klein et al. 2018, Álvarez-Fernández and Malumbres 2020, Petroni et al. 2020).

Literature References

PubMed ID	Title	Journal	Year
25633797	The history and future of targeting cyclin-dependent kinases in cancer therapy Asghar, U, Witkiewicz, AK, Turner, NC, Knudsen, ES	Nat Rev Drug Discov	2015
32346095	Immunomodulation by anticancer cell cycle inhibitors Petroni, G, Formenti, SC, Chen-Kiang, S, Galluzzi, L	Nat Rev Immunol	2020
29731395	CDK4/6 Inhibitors: The Mechanism of Action May Not Be as Simple as Once Thought Klein, ME, Kovatcheva, M, Davis, LE, Tap, WD, Koff, A	Cancer Cell	2018
32289274	Mechanisms of Sensitivity and Resistance to CDK4/6 Inhibition Alvarez-Fernández, M, Malumbres, M	Cancer Cell	2020