Loading
Cell division runs on a clock made of cyclins and their kinases (CDKs), each pair firing in order: D-CDK4/6 to leave rest, E-CDK2 to start copying DNA, A-CDK2 to finish, B-CDK1 to divide. Cancers speed the clock; CDK inhibitors slow it.
Mitogens induce cyclin D, which with CDK4/6 mono-phosphorylates RB; cyclin E-CDK2 completes RB hyperphosphorylation, releasing E2F and committing the cell at the restriction point (the point of no return). Cyclin A-CDK2 drives S phase, cyclin A/B-CDK1 drive G2 and mitosis, with CDK1 activation controlled by WEE1/PKMYT1 (inhibitory phosphorylation) and CDC25 phosphatases. CDK7 (CAK) activates all CDKs and also drives transcription. INK4 proteins (p16 from CDKN2A) inhibit CDK4/6; CIP/KIP (p21, p27) inhibit CDK2; APC/C and SCF ubiquitin ligases destroy cyclins in order. Cancer alterations: CCND1 amplification, CDK4 amplification (liposarcoma), CDKN2A deletion (very common, also removes ARF), CCNE1 amplification (ovarian, gastric, endocrine-resistant breast), RB1 loss (SCLC, TNBC, resistant prostate). CDK4/6 inhibitors need intact RB; CCNE1 amplification and RB1 loss are the escape routes and the rationale for CDK2 inhibitors and CDK4-selective atirmociclib.
An engine with four cylinders that must fire in sequence. Cyclins are the fuel injected into each cylinder in turn and burned away; CDKs are the pistons. p16 and p21 are the hand on the throttle. Cancers flood the first cylinder (cyclin D) or remove the throttle hand (CDKN2A).
It fills the gap between the primary-tumour atlases and the castration-resistant series by describing the disease at the moment most treatment decisions are actually made, and it identifies SPOP as a favourable marker rather than a neutral one.
MYC amplification, present in a fifth to a third of TNBC, is undruggable directly; this is the synthetic-lethal logic behind CDK (especially CDK9 and CDK1/2) inhibitor trials in the disease.
One pathway page on OnCo cites this paper by its DOI; this record gives the citation a page of its own so a reader can follow it without leaving OnCo. Read the abstract above alongside the citing page listed under Related; the record was created automatically from the Europe PMC entry and its figures have not been checked by hand.
This review is the textbook basis for the cyclin D-CDK4/6-RB axis that palbociclib, ribociclib and abemaciclib target in breast cancer, and for reading CDKN2A loss and cyclin D1 amplification in tumour genomes.
This paper closed the loop between DNA damage, p53 and the cell cycle machinery. p21 is now a standard marker of p53 activity, part of how chemotherapy and radiotherapy stop cells dividing, and a component of the senescence response that CDK4/6 inhibitors exploit.
Shares Hallmark: evading growth suppressors, CDKN1A, WEE1, DNA replication stress and the tags mechanism, mechanics-atlas.
Shares Oestrogen receptor signalling, Small cell lung cancer (KEGG map), MYC, Estrogen receptor (ERα) and the tags mechanism, mechanics-atlas.
Shares MYC pathway activation in triple-negative breast cancer is synthetic lethal with CDK inhibition, WEE1, DNA replication stress, TP53 and the tags mechanism, mechanics-atlas.
Shares MYC, CDK4/6, p53 / RB / cell-cycle checkpoint, Burkitt lymphoma and the tags mechanism, mechanics-atlas.
Shares Small cell lung cancer (KEGG map), Non-small cell lung cancer (KEGG map), p53 / RB / cell-cycle checkpoint, TP53 and the tags mechanism, mechanics-atlas.
Shares WEE1, DNA replication stress, Gallbladder cancer, Ovarian cancer and the tags mechanism, mechanics-atlas.
Shares Estrogen receptor (ERα), Ovarian cancer, HR-positive / HER2-negative breast cancer and the tags mechanism, mechanics-atlas.
Shares Estrogen receptor (ERα), Mantle cell lymphoma, HR-positive / HER2-negative breast cancer and the tags mechanism, mechanics-atlas.