The cell-cycle engine (cyclins & CDKs)
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.
In one picture
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).
Diagram
top- CDK4/6 inhibitors (palbociclib, ribociclib, abemaciclib) in HR+ breast cancer; CDK4-selective atirmociclib to spare neutrophils
- CDK2 inhibitors for CCNE1-amplified and CDK4/6-resistant disease (trials)
- WEE1 (azenosertib) and PKMYT1 (lunresertib) inhibitors force premature mitosis in CCNE1-amplified or TP53-mutant cells
- CDK7 and CDK9 inhibitors hit transcription as well as the cycle
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