Introduction

Antibody-mediated blockade of the epidermal growth factor receptor (EGFR) by cetuximab or panitumumab is the only clinically approved targeted therapy against transformed cells in metastatic colorectal cancer (mCRC). Administration of cetuximab or panitumumab is poorly guided by molecular criteria: no genetic predictors of sensitivity are available and the only predictors of resistance are mutations in the KRAS and NRAS genes.

Technical features

By coupling next-generation DNA sequencing with pharmacological experiments in mice bearing mCRC samples from patient donors, we have identified genetic alterations that specifically segregate with response or resistance to EGFR antibodies. Responsive cases are enriched for amplification and mutations in the IRS2 gene. Resistant cases include genetic alterations in HER2, EGFR, FGFR1, PDGFRA, and MAP2K1. These resistance-associated genes encode therapeutically actionable proteins, the pharmacological inhibition of which leads to tumour growth inhibition or tumour regression in mice. This data-set provides a systematic approach to evaluating response to EGFR blockade in colorectal cancer, with important diagnostic and therapeutic implications.

Possible Applications

• Colorectal cancer diagnosis and treatment;

Advantages

• Genetic selection of patients potentially responsive to EGFR antibodies;
• Genetic selection of patients likely to be resistant to EGFR antibodies;
• Genetic selection of patients potentially responsive to alternative therapies;
• New tretaments for currently untreatable patients.