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Cells tag unwanted proteins with a small marker called ubiquitin and feed them into a shredder, the proteasome. Myeloma cells, which make antibody in bulk, die if the shredder jams; and the newest drugs hijack the tagging machinery to make a cancer destroy its own oncoproteins.
E1 activates ubiquitin, E2 carries it, and one of ~600 E3 ligases (CRL4-CRBN, VHL, MDM2, SCF-FBXW7, APC/C) attaches it to a substrate lysine; K48 chains send substrates to the 26S proteasome, whose β5 subunit is the target of bortezomib, carfilzomib and ixazomib. Deubiquitinases (USP7, USP14) reverse tagging. Plasma cells and myeloma depend on proteasome capacity to clear misfolded immunoglobulin; inhibition triggers the unfolded protein response (PERK, IRE1, ATF6) and death, and stabilises IκB to shut NF-κB. Cereblon modulators (thalidomide, lenalidomide, pomalidomide; CELMoDs iberdomide, mezigdomide, golcadomide) are molecular glues that redirect CRL4-CRBN to degrade IKZF1/3. PROTACs (vepdegestrant for ER, ARV-766 for AR, BGB-16673 for BTK) link a target ligand to an E3 ligand. Oncogenic lesions in the system: FBXW7 loss stabilises MYC, cyclin E and NOTCH; SPOP mutations in prostate; VHL loss stabilises HIF; MDM2 amplification degrades p53. HSP90 and chaperones buffer mutant kinases; HSP90 inhibitors mostly failed on toxicity.
A recycling plant with barcode stickers (ubiquitin) and a shredder (proteasome). Myeloma is a paper mill that produces so much waste it dies when the shredder stops (bortezomib). PROTACs and glues are forged stickers that get the plant to shred the cancer's own machinery.
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It is the quantitative answer to why prostate cancer has so few targeted therapies. The common events are not druggable, the druggable ones are individually rare, and no trial can be powered on a driver present in 2% of men without an international basket.
The reference classification of prostate cancer as it presents, and the source of the two numbers that drive most molecular treatment decisions in the disease: a quarter with a PI3K or MAPK lesion, which is the rationale for capivasertib in PTEN-deficient disease, and a fifth with DNA repair inactivation, which is the rationale for PARP inhibitors.
It established the fusion-negative side of the prostate cancer taxonomy and made SPOP the disease's signature point mutation, in a ubiquitin ligase adaptor rather than in a kinase, which is part of why prostate cancer has so few druggable drivers.
It put RNF43 on the pancreatic driver list and gave cyst fluid testing a way to separate the harmless serous cyst from the mucinous ones that need watching.
Shares IKZF1 (Ikaros), IKZF3 (Aiolos), Vepdegestrant, MYC and the tags mechanism, mechanics-atlas.
Shares VHL / HIF oxygen sensing, HIF-2α, The p53 network (guardian of the genome), Prostate cancer and the tags mechanism, mechanics-atlas.
Shares VHL / HIF oxygen sensing, HIF-2α and the tags mechanism, mechanics-atlas.
Shares VHL / HIF oxygen sensing, HIF-2α and the tags mechanism, mechanics-atlas.
Shares BTK (Bruton tyrosine kinase), BCMA, Estrogen receptor (ERα), Androgen receptor and the tags mechanism, mechanics-atlas.
Shares VHL / HIF oxygen sensing, HIF-2α and the tags mechanism, mechanics-atlas.
Shares Estrogen receptor (ERα), HR-positive / HER2-negative breast cancer, Prostate 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.