Cell Cycle Basics
Cytarabine and methotrexate kill cells mainly in this phase.
What is S phase?
S phase is DNA replication.
Overexpression of this cyclin through t(11;14) defines mantle cell lymphoma.
What is cyclin D1?
Diffuse staining for this INK4 protein serves as a surrogate marker for HPV-driven oropharyngeal cancer.
What is p16^INK4A?
Knudson’s two-hit hypothesis came from studying this pediatric tumor.
What is retinoblastoma?
Kaposi sarcoma, primary effusion lymphoma, and multicentric Castleman disease are all caused by this virus, which carries its own cyclin D gene.
What is HHV-8 (KSHV)?
The viral cyclin pairs with CDK6 and resists p16, p21, and p27. That lets it phosphorylate pRb without any mitogen signal.
Vincristine and paclitaxel disrupt microtubules, so they act in this phase.
What is M phase?
Estrogen receptor signaling drives this cyclin, which is why CDK4/6 inhibitors are paired with endocrine therapy in HR+ breast cancer.
What is cyclin D1?
D-type cyclins connect extracellular signals to the clock.
Besides p16, the CDKN2A locus encodes this regulator of the p53 pathway.
What is p14^ARF?
One deletion can disable both the pRb and p53 pathways.
Mechanism by which HPV-positive tumors overexpress p16.
What is E7 inactivating pRb, which removes the feedback that normally limits p16?
The CDK inhibitor is high, but the target it protects is gone.
MYC can’t bind DNA or drive the cell cycle until it dimerizes with this partner protein.
What is MAX?
When MAD binds MAX instead, the complex represses MYC targets and favors differentiation.
CML and AML stem cells survive imatinib and cytarabine partly by resting in this state.
What is G0 (quiescence)?
G0 cells sit outside the cycling clock that most chemotherapy targets.
Hematopoietic progenitors depend more on this CDK, so the more CDK4-selective abemaciclib causes less neutropenia than palbociclib.
What is CDK6?
Germline CDKN2A mutations cause this syndrome, which carries melanoma and pancreatic cancer risk.
What is FAMMM (familial atypical multiple mole melanoma) syndrome?
Acquired loss of this gene makes HR+ breast cancer resistant to palbociclib.
What is RB1?
With no pRb, blocking the upstream kinase does nothing.
In MSI-high colorectal cancer, including Lynch syndrome, a frameshift in a poly-A tract inactivates this TGF-β pathway gene in most tumors.
What is TGFBR2?
Loss of the receptor removes TGF-β–induced G1 arrest.
CDK4/6 inhibitors can only arrest cells that haven’t yet passed this late-G1 commitment point, defined by Pardee.
What is the restriction (R) point?
Nearly all myelomas dysregulate at least one D-type cyclin, which forms the basis of this classification.
What is the TC (translocation/cyclin D) classification?
In CLL, newly acquired CDKN2A loss, often with TP53 disruption, is a hallmark of this complication.
What is Richter transformation?
Trilaciclib, given before chemotherapy in small cell lung cancer, pauses the marrow in G1 but leaves the tumor unprotected.
What is near-universal RB1 loss in SCLC?
In adult T-cell leukemia/lymphoma, which is common in patients from Japan and the Caribbean, this HTLV-1 protein binds p16 and p15 and blocks their inhibition of CDK4.
What is Tax?
Disabling the INK4 brake frees cyclin D–CDK4 to phosphorylate pRb.
Amplification of this gene lets tumors bypass cyclin D–CDK4/6 and drive the E2F feedback loop directly, causing resistance to CDK4/6 inhibitors.
What is CCNE1 (cyclin E1)?
Cyclin E–CDK2 completes pRb phosphorylation and locks in passage through the R point.
TP53-mutant tumors lack a functional G1 checkpoint and depend on G2/M arrest, so investigators are testing inhibitors of this kinase, which adds the inhibitory phosphate to CDK1.
What is Wee1 (for example, adavosertib)?
Wee1 adds the inhibitory phosphate and Cdc25 removes it.
Homozygous CDKN2A deletion occurs in most cases of this acute leukemia.
What is T-ALL?
Losing INK4 frees CDK4/6 to phosphorylate pRb unchecked
EGFR-mutant NSCLC can relapse after osimertinib by transforming into this histology, and baseline RB1/TP53 co-loss predicts the risk.
What is small cell (neuroendocrine) transformation?
pRb loss enables lineage plasticity, not just proliferation.
Loss of this Smad-pathway protein lets pancreatic cancer escape TGF-β–induced arrest through p15 and p21.
What is SMAD4 (DPC4)?
TGF-β normally induces p15 and p21, represses MYC, and frees p27.