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 Witkiewicz, AK, Asghar, U, 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 Tap, WD, Davis, LE, Koff, A, Kovatcheva, M, Klein, ME	Cancer Cell	2018
32289274	Mechanisms of Sensitivity and Resistance to CDK4/6 Inhibition Alvarez-Fernández, M, Malumbres, M	Cancer Cell	2020