# The molecular evolution of acquired resistance to targeted EGFR blockade in colorectal cancers

Source: https://onco.cc/key-papers/paper-diaz-molecular-evolution-egfr-resistance-colorectal-nature-2012/  
OnCo record `paper-diaz-molecular-evolution-egfr-resistance-colorectal-nature-2012` (Key paper). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

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.

## Fields

- Kind: Key paper
- Last checked: 2026-09-24
- Journal: Nature
- Year: 2012
- DOI: 10.1038/nature11219
- Authors: Diaz LA, Williams RT, Wu J, et al.
- 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.
- What it means: 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.

## Sources

- Diaz et al., Nature 2012: the molecular evolution of acquired resistance to EGFR blockade (28 panitumumab patients): https://doi.org/10.1038/nature11219
- PubMed: https://pubmed.ncbi.nlm.nih.gov/22722843/

## Connected records

- cancers: [Colorectal cancer](https://onco.cc/cancers/colorectal/)
- technologies: [Liquid biopsy (ctDNA)](https://onco.cc/technologies/liquid-biopsy/)
- targets: [EGFR](https://onco.cc/targets/egfr/), [KRAS](https://onco.cc/targets/kras/)
- drugs: [Guardant360 CDx](https://onco.cc/drugs/guardant360-cdx/), [Panitumumab](https://onco.cc/drugs/panitumumab/)
- institutions: [Johns Hopkins Hospital / Sidney Kimmel Comprehensive Cancer Center](https://onco.cc/institutions/johns-hopkins/)
- pathways: [Clonal evolution & minimal residual disease](https://onco.cc/pathways/clonal-evolution/), [RAS / RAF / MEK / ERK (MAPK)](https://onco.cc/pathways/ras-mapk/)
- terms: [Cell-free DNA (cfDNA)](https://onco.cc/terms/cfdna/), [Circulating tumour DNA (ctDNA)](https://onco.cc/terms/ctdna/)
- people: [Bert Vogelstein](https://onco.cc/people/bert-vogelstein/), [Kenneth W. Kinzler](https://onco.cc/people/kenneth-kinzler/), [Luis A. Diaz Jr.](https://onco.cc/people/luis-diaz/)
- journals: [Nature](https://onco.cc/journals/nature/)

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