# Emergence of KRAS mutations and acquired resistance to anti-EGFR therapy in colorectal cancer

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

## TL;DR

Bowel cancers that respond to cetuximab almost always stop responding within a year. This paper showed why: KRAS-mutant cells take over, and their DNA shows up in the blood months before a scan changes.

## Summary

Molecular alterations of KRAS, in most instances point mutations, were shown to be causally associated with the onset of acquired resistance to anti-EGFR treatment in colorectal cancers. Expressing mutant KRAS under the control of its endogenous promoter was sufficient to confer cetuximab resistance, but resistant cells remained sensitive to combined inhibition of EGFR and MEK. Analysis of metastases from patients who developed resistance to cetuximab or panitumumab showed the emergence of KRAS amplification in one sample and acquisition of secondary KRAS mutations in 6 of 10 cases. KRAS mutant alleles were detectable in the blood of cetuximab-treated patients as early as 10 months before radiographic documentation of disease progression.

## Fields

- Kind: Key paper
- Last checked: 2026-09-24
- Journal: Nature
- Year: 2012
- DOI: 10.1038/nature11156
- Authors: Misale S, Yaeger R, Hobor S, et al.
- Findings: Secondary KRAS mutations in 6 of 10 patients progressing on an EGFR antibody, plus one KRAS amplification.; Mutant KRAS alleles detectable in blood up to 10 months before radiographic progression.; Resistant cells remained sensitive to combined EGFR and MEK inhibition.
- What it means: It made acquired resistance a measurable, plasma-readable event, and it is the origin of anti-EGFR rechallenge strategies guided by ctDNA clearance of the resistant clone.
- Caveats: Small patient numbers behind the clinical observations.; The EGFR plus MEK combination has not succeeded clinically.; KRAS is only one of several resistance routes, alongside NRAS, BRAF, EGFR ectodomain and HER2 or MET amplification.

## Sources

- Misale et al., Nature 2012: emergence of KRAS mutations and acquired resistance to anti-EGFR therapy: https://doi.org/10.1038/nature11156
- PubMed: https://pubmed.ncbi.nlm.nih.gov/22722830/

## 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: [Cetuximab](https://onco.cc/drugs/cetuximab/), [Panitumumab](https://onco.cc/drugs/panitumumab/)
- institutions: [Istituto di Candiolo IRCCS (FPO)](https://onco.cc/institutions/candiolo/), [Niguarda Cancer Center, ASST Grande Ospedale Metropolitano Niguarda](https://onco.cc/institutions/niguarda-cancer-center/)
- pathways: [Clonal evolution & minimal residual disease](https://onco.cc/pathways/clonal-evolution/), [RAS / RAF / MEK / ERK (MAPK)](https://onco.cc/pathways/ras-mapk/), [Resistance routes: how a blocked pathway comes back](https://onco.cc/pathways/resistance-routes-map/)
- terms: [Cell-free DNA (cfDNA)](https://onco.cc/terms/cfdna/), [Circulating tumour DNA (ctDNA)](https://onco.cc/terms/ctdna/)
- people: [Alberto Bardelli](https://onco.cc/people/alberto-bardelli/), [Andrea Sartore-Bianchi](https://onco.cc/people/andrea-sartore-bianchi/), [Rona Yaeger](https://onco.cc/people/rona-yaeger/), [Salvatore Siena](https://onco.cc/people/salvatore-siena/)
- journals: [Nature](https://onco.cc/journals/nature/)

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