Protein homeostasis and the proteasome
Unwanted proteins are tagged with ubiquitin and fed into a shredder. Myeloma dies when the shredder jams; and the newest drugs forge the tags so that a cancer destroys its own oncoproteins.
Diagram
Pick a product above a diagram to see the nodes it hits and the escape routes below the block. Hover or tap any node or arrow for what it is; every node opens its target, glossary entry or the pathway page. Violet boxes are druggable targets.
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.
What happens
In plain words, then the glossary entries the stage rests on. Chapter 3, Replication and growth machinery: Cancer cells use the same engine as normal cells, only stuck at full throttle.
Unwanted proteins are tagged with ubiquitin and fed into a shredder. Myeloma dies when the shredder jams; and the newest drugs forge the tags so that a cancer destroys its own oncoproteins.
Ubiquitin-proteasome system & protein homeostasis. 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.
The molecular players
The proteins and genes at this stage, with their role and how many products act on each. Listed players come from the atlas; drawn players sit as nodes in the diagrams above.
The hormone switch that drives most breast cancers. Blocking or destroying it is the oldest and most effective targeted therapy.
The signalling enzyme that B-cell cancers use to survive. Blocking it turned chronic lymphocytic leukaemia into a disease controlled by a daily pill.
MDM2 is the protein that degrades p53; blocking it reactivates p53 in tumours where the gene is intact, especially the liposarcomas that carry extra copies of MDM2.
A master switch that kidney cancer cells leave permanently on when they lose the VHL gene; belzutifan blocks it.
Where medicines act
Products grouped by the node they hit, most advanced first, with the cancers an approved product is linked to. Pick one above the diagram to see it light up.
- VepdegestrantApprovedHR-positive / HER2-negative breast cancerHR-positive metastatic breast cancer after CDK4/6 inhibitors
- CamizestrantApprovedHR-positive / HER2-negative breast cancerHR-positive metastatic breast cancer after CDK4/6 inhibitors
- ElacestrantApprovedHR-positive / HER2-negative breast cancerHR-positive metastatic breast cancer after CDK4/6 inhibitors
- ExemestaneApprovedHR-positive / HER2-negative breast cancerHigh-risk early HR-positive breast cancer
- Fluoroestradiol F-18 (FES PET)ApprovedHR-positive / HER2-negative breast cancer
- FulvestrantApprovedHR-positive / HER2-negative breast cancer
- Goserelin / leuprolide (ovarian function suppression)ApprovedHR-positive / HER2-negative breast cancerHigh-risk early HR-positive breast cancer
- Guardant360 CDxApprovedNon-small-cell lung cancerHR-positive / HER2-negative breast cancer
- +9 more at Estrogen receptor (ERα) →
- AcalabrutinibApprovedChronic lymphocytic leukaemiaDiffuse large B-cell lymphomaChronic lymphocytic leukaemia, first treatment
- IbrutinibApprovedChronic lymphocytic leukaemiaDiffuse large B-cell lymphoma
- OrelabrutinibApprovedChronic lymphocytic leukaemiaMantle cell lymphoma
- PirtobrutinibApprovedChronic lymphocytic leukaemiaDiffuse large B-cell lymphomaRelapsed or refractory chronic lymphocytic leukaemia
- ZanubrutinibApprovedChronic lymphocytic leukaemiaDiffuse large B-cell lymphomaMarginal zone lymphoma
- BexobrutidegPhase 3
- BGB-16673Phase 3
- NemtabrutinibPhase 3
- BrigimadlinPhase 3
- KRT-232Phase 2
- BortezomibApprovedMultiple myelomaNewly diagnosed multiple myeloma, transplant-eligiblePlasma cell leukaemia
- CarfilzomibApprovedMultiple myelomaRelapsed or refractory multiple myeloma
- LenalidomideApprovedMultiple myelomaDiffuse large B-cell lymphomaNewly diagnosed multiple myeloma, transplant-ineligible
- PomalidomideApprovedMultiple myelomaKaposi sarcomaRelapsed or refractory multiple myeloma
- IberdomideApprovedMultiple myeloma
- MezigdomidePhase 3
How tumours escape
Records tied to this stage that describe resistance, evasion or tolerance. The resistance atlas lists the routes class by class.
- early clinicalBTK degraders to pre-empt resistance in frontline CLL
If destroying BTK works when every inhibitor has failed, using it first might stop resistance from ever emerging.
- preclinical evidenceresearchLook for the resistant sub-population before the first dose
Resistance mutations often exist in a tiny fraction of cells before treatment starts. Error-corrected sequencing that detects variants below 0.01 percent allele fraction could find them at diagnosis and prompt a mechanism-matched combination from day one.
- speculativeresearchVaccinate against the resistance mutation before it takes over
Resistance often arrives as the same few mutations. Teaching the immune system to recognise them in advance could remove the escaping cells while they are still rare.
- 2024rctNATALEE: three years of ribociclib after surgery in a broad population of hormone-receptor-positive early breast cancerNew England Journal of Medicinechanged practice
Measured by
Biomarkers, tests and assays in the corpus that read this stage in a patient.
Open questions
What is not known at this stage: the atlas's own questions, the bottlenecks it bears on, and the ideas in the corpus that try to answer them.
- How many of the ~600 E3 ligases can be recruited by glues, and do tissue-restricted ligases give tumour selectivity?
- Will degraders beat inhibitors on resistance, or just move it?
Key evidence
Papers in the corpus tied to this stage's pathways, targets and terms, newest first.
- 2025rctAMPLIFY: fixed-duration acalabrutinib plus venetoclax, with or without obinutuzumab, versus chemo-immunotherapy in fit CLL patientsNew England Journal of Medicinechanged practice
- 2024rctNATALEE: three years of ribociclib after surgery in a broad population of hormone-receptor-positive early breast cancerNew England Journal of Medicinechanged practice
- 2022reviewPROTAC targeted protein degraders: the past is prologueNature Reviews Drug Discovery
- 2020rctELEVATE-TN: acalabrutinib, alone or with obinutuzumab, against chemo-immunotherapy in untreated CLLThe Lancetchanged practice
- 2020rctmonarchE: two years of abemaciclib after surgery in high-risk, hormone-receptor-positive early breast cancerJournal of Clinical Oncologychanged practice
- 2020translationalZUMA-2: brexu-cel CAR-T for mantle cell lymphoma that has failed BTK inhibitorsNew England Journal of Medicinechanged practice
- 2015rctIBIS-I: five years of tamoxifen keeps preventing breast cancer for at least 20 yearsLancet Oncologychanged practice
- 2010observationalSubtype-specific genomic alterations define new targets for soft-tissue sarcoma therapyNature Genetics
- 2001basicThe first PROTAC: a chimeric molecule that tags a protein for destructionPNAS
- 2000reviewVogelstein, Lane and Levine 2000: surfing the p53 networkNature
- 1997reviewLevine 1997: p53, the cellular gatekeeper for growth and divisionCell
src/data/mechanics-atlas.ts). Players, medicines, escape routes, tests, ideas and papers are resolved from the knowledge graph at build time through the stage's pathways, targets and terms, so every item here has its own page and sources. Where a section is missing, the corpus has no record tied to the stage yet. Nothing here is medical advice; see about and methodology. Stage 3.8 of 56.