Autophagy
Under famine or drug stress a cell eats its own components to survive. KRAS-driven cancers depend on it, and it also destroys the molecules that display antigens to T cells.
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 besieged city that starts recycling furniture into firewood. It keeps the lights on through the siege, and burning the 'wanted posters' (MHC) hides its criminals too.
What happens
In plain words, then the glossary entries the stage rests on. Chapter 4, Evading death and repair: To survive the damage they generate and the treatments thrown at them, cancer cells rewire death and repair.
Under famine or drug stress a cell eats its own components to survive. KRAS-driven cancers depend on it, and it also destroys the molecules that display antigens to T cells.
Autophagy. Autophagy is the cell's recycling programme. Cancer cells, especially pancreatic and RAS-driven tumours, use it to survive starvation and drug stress, which is why hydroxychloroquine, an old malaria drug that blocks it, keeps appearing in trials.
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.
KRAS is the most commonly mutated cancer gene, called 'undruggable' for 40 years until 2021.
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.
- AdagrasibApprovedNon-small-cell lung cancerColorectal cancerPancreatic ductal adenocarcinoma
- Avutometinib + defactinibApprovedOvarian cancerLow-grade serous ovarian cancer
- DaraxonrasibApprovedPancreatic ductal adenocarcinomaMetastatic pancreatic ductal adenocarcinomaKRAS G12C-mutant pancreatic ductal adenocarcinoma
- FulzerasibApprovedNon-small-cell lung cancer
- GarsorasibApprovedNon-small-cell lung cancerKRAS G12C-mutant non-small-cell lung cancer
- GlecirasibApprovedNon-small-cell lung cancerKRAS G12C-mutant non-small-cell lung cancer
- Guardant360 CDxApprovedNon-small-cell lung cancerHR-positive / HER2-negative breast cancer
- Resolution ctDx FIRSTApprovedNon-small-cell lung cancer
- +16 more at KRAS →
How tumours escape
Records tied to this stage that describe resistance, evasion or tolerance. The resistance atlas lists the routes class by class.
- early clinicalindustryAdd the second drug on day one when the escape route is predictable
If most tumours escape a drug by the same back-up route, blocking that route from the start may prevent resistance rather than chase it.
- 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.
- 2023rctCodeBreaK 300: sotorasib plus panitumumab in chemotherapy-refractory KRAS G12C colorectal cancerNew England Journal of Medicinechanged practice
- 2020basicAutophagy promotes immune evasion of pancreatic cancer by degrading MHC-INature
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.
- Does hydroxychloroquine with MEK/KRAS inhibition help patients (trials in pancreatic cancer)?
- Is autophagy inhibition safe long-term for neurons and muscle?
- early clinicalindustryAn open-science consortium on the undruggable drivers, open until a candidate
Companies and public funders would pool money and scientists to crack the hardest cancer proteins, such as MYC and mutant p53, sharing everything openly until there is a real drug candidate, then competing on the final product.
- early clinicalindustryCovalent chemistry for the RAS mutations that still have no drug
One RAS mutation can now be drugged because it offers a reactive handle. Most RAS mutations do not, so new chemistry is needed to grab other amino acids.
- early clinicalMaking microsatellite-stable colorectal cancer immunotherapy-responsive
Ninety-five percent of bowel cancers ignore immunotherapy. Combinations that heat the tumour up (targeted drugs, radiation, new checkpoints) are the main hope.
- early clinicalOff-the-shelf KRAS vaccines after pancreatic cancer surgery
Almost every pancreatic cancer shares one of a handful of KRAS mutations. A pre-made vaccine against them could be given to every patient after surgery.
- early clinicalRAS(ON) inhibitors to convert unresectable pancreatic cancer to resectable
If daraxonrasib shrinks metastatic tumours this well, use it before surgery to make more locally advanced tumours operable.
- preclinical evidenceresearchA synthetic lethality map for every cancer driver in every tissue context
For each cancer-causing mutation, find every gene the cancer cell newly depends on, in every tissue, so that even undruggable drivers get druggable partners.
- preclinical evidenceresearchAn open degrader consortium against every undruggable driver transcription factor
Cancer's most important drivers, such as MYC and mutant p53, cannot be blocked with normal drugs. Pool effort and share results openly to build molecules that destroy them instead.
- preclinical evidenceindustryAntibodies that see mutant KRAS and p53 fragments displayed on the cell surface
Cells chop up their internal proteins and display the pieces on their surface. That means even undruggable proteins inside the cell can be attacked from outside by the immune system.
- preclinical evidenceengineeringSelf-driving laboratories that run the cancer biology hypothesis loop autonomously
Robotic labs guided by AI that design experiments on tumour models, run them, read the results and design the next ones, around the clock, with every result published openly.
- preclinical evidenceresearchTurn a brake back on: drugs that reactivate the PP2A phosphatase
Cells have an enzyme, PP2A, that removes the growth signals cancer relies on. Cancers switch it off. Drugs that switch it back on are an unusual and largely untried approach.
2 more ideas are linked to this stage's pathways, targets and terms; see the rankings →
Key evidence
Papers in the corpus tied to this stage's pathways, targets and terms, newest first.
- 2026reviewKRYSTAL-12 plain language summary: adagrasib for non-small-cell lung cancer with KRAS G12C mutationsFuture Oncology
- 2023rctCodeBreaK 200: sotorasib versus docetaxel in KRAS G12C-mutated lung cancer, a modest win for the first KRAS drugThe Lancetchanged practice
- 2023rctCodeBreaK 300: sotorasib plus panitumumab in chemotherapy-refractory KRAS G12C colorectal cancerNew England Journal of Medicinechanged practice
- 2021reviewFDA's Project Optimus manifesto: cancer drugs are approved at doses that are too highNew England Journal of Medicinechanged practice
- 2020basicAutophagy promotes immune evasion of pancreatic cancer by degrading MHC-INature
- 2013reviewCancer genome landscapes: about 140 driver genes, and each tumour needs only a handfulScience
- 2013basicOstrem and Shokat: the hidden pocket that made KRAS G12C druggableNature
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 4.3 of 56.