{"entity":{"id":"paper-diaz-molecular-evolution-egfr-resistance-colorectal-nature-2012","kind":"paper","name":"The molecular evolution of acquired resistance to targeted EGFR blockade in colorectal cancers","aka":[],"tldr":"Published beside the paper above: resistance to EGFR antibodies does not have to be invented, it is already there. Rare KRAS-mutant cells present before treatment expand under it, on a schedule a mathematical model predicts.","summary":"The hypothesis that rare cells with KRAS mutations pre-exist at low levels in tumours with ostensibly wild-type KRAS genes was tested by looking for mutant KRAS DNA in the circulation of 28 patients receiving monotherapy with panitumumab. Of 24 patients whose tumours were initially KRAS wild-type, 9 (38%) developed detectable KRAS mutations in their serum, three of them multiple different mutations. The appearance of the mutations was consistent, generally occurring between 5 and 6 months after starting treatment. Mathematical modelling indicated that the mutations were present in expanded subclones before panitumumab was begun, explaining why solid tumours develop resistance to targeted therapies in a highly reproducible fashion.","asOf":"2026-09-24","links":[{"label":"Diaz et al., Nature 2012: the molecular evolution of acquired resistance to EGFR blockade (28 panitumumab patients)","url":"https://doi.org/10.1038/nature11219"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/22722843/"}],"tags":[],"related":[],"cancers":["colorectal"],"sections":[],"technologies":["liquid-biopsy"],"targets":["kras","egfr"],"drugs":["panitumumab"],"companies":[],"institutions":["johns-hopkins"],"pathways":["clonal-evolution","ras-mapk"],"terms":["ctdna","cfdna"],"trials":[],"people":["luis-diaz","bert-vogelstein","kenneth-kinzler"],"bottlenecks":[],"keyPapers":[],"journals":["nature"],"dependsOn":[],"notes":[],"journal":"Nature","year":2012,"doi":"10.1038/nature11219","pmid":"22722843","authors":"Diaz LA, Williams RT, Wu J, et al.","paperType":"translational","findings":["KRAS mutations appeared in the serum of 9 of 24 initially wild-type patients (38%), generally 5 to 6 months into treatment.","Modelling placed the resistant subclones in the tumour before treatment started."],"whatItMeans":"It reframed resistance as selection rather than mutation, which is why the field now asks how to suppress a pre-existing clone rather than how to prevent a new mutation, and why ctDNA is the natural monitoring tool.","caveats":["28 patients on monotherapy; modern practice uses combinations.","Serum rather than plasma, with the assay sensitivity of 2012.","KRAS is one of several resistance mechanisms."],"changedPractice":false,"participants":28},"route":"/key-papers/paper-diaz-molecular-evolution-egfr-resistance-colorectal-nature-2012/","neighbours":{"cancer":[{"id":"colorectal","kind":"cancer","name":"Colorectal cancer","route":"/cancers/colorectal/"}],"technology":[{"id":"liquid-biopsy","kind":"technology","name":"Liquid biopsy (ctDNA)","route":"/technologies/liquid-biopsy/"}],"target":[{"id":"egfr","kind":"target","name":"EGFR","route":"/targets/egfr/"},{"id":"kras","kind":"target","name":"KRAS","route":"/targets/kras/"}],"drug":[{"id":"guardant360-cdx","kind":"drug","name":"Guardant360 CDx","route":"/drugs/guardant360-cdx/"},{"id":"panitumumab","kind":"drug","name":"Panitumumab","route":"/drugs/panitumumab/"}],"institution":[{"id":"johns-hopkins","kind":"institution","name":"Johns Hopkins Hospital / Sidney Kimmel Comprehensive Cancer Center","route":"/institutions/johns-hopkins/"}],"pathway":[{"id":"clonal-evolution","kind":"pathway","name":"Clonal evolution & minimal residual disease","route":"/pathways/clonal-evolution/"},{"id":"ras-mapk","kind":"pathway","name":"RAS / RAF / MEK / ERK (MAPK)","route":"/pathways/ras-mapk/"}],"term":[{"id":"cfdna","kind":"term","name":"Cell-free DNA (cfDNA)","route":"/terms/cfdna/"},{"id":"ctdna","kind":"term","name":"Circulating tumour DNA (ctDNA)","route":"/terms/ctdna/"}],"person":[{"id":"bert-vogelstein","kind":"person","name":"Bert Vogelstein","route":"/people/bert-vogelstein/"},{"id":"kenneth-kinzler","kind":"person","name":"Kenneth W. Kinzler","route":"/people/kenneth-kinzler/"},{"id":"luis-diaz","kind":"person","name":"Luis A. Diaz Jr.","route":"/people/luis-diaz/"}],"journal":[{"id":"nature","kind":"journal","name":"Nature","route":"/journals/nature/"}]}}