Colorectal cancer causes more than 600,000 deaths annually over the world. A group of scientists from the IMIM-Hospital del Mar, lead by Joan Albanell, have now identified a mutation that confers resistance to cetuximab, one of the drugs used to treat this cancer.
Cetuximab and panitumumab are two antibodies against epidermal growth factor receptor (EGFR), and both are widely used to treat colorectal cancer. EGFR is a transmembrane protein which is amplified in these tumours. The antibodies bind to the extracellular domain of the EGFR preventing its activation. This results in halting of the cascade of intracellular signals dependent on this receptor and therefore in slowing down of the cancer.
More than 80% of patients with cancer have EGFR increased in their tumor cells, so these antibodies are very widely used, in combination with chemotherapy or radiotherapy, and they prolong survival of the patients.
Unfortunately, patients eventually develop resistance to these agents. In this paper published in Nature Medicine, the researchers took cetuximab-sensitive cells and treated them continuously with the drug. After five months some resistant clones had appeared. These were sequenced and the S492R mutation was identified in all of them, in the extracellular domain of EGFR. Some in vitro biochemical analysis followed, which showed that the S492R mutant EGFR could not bind cetuximab anymore, although it did bind panitumumab.
The authors then checked some real samples of colorectal cancer, and although they could not find this mutation in any of 256 analysed samples from patients who had not received treatment, two out of ten subjects who had disease progression after cetuximab treatment had acquired the mutation S492R.
Therefore, this mutation prevents cetuximab binding and confers resistance to cetuximab, but cells retain binding to and are growth inhibited by panitumumab. Indeed, a subject with cetuximab resistance harboring the S492R mutation responded to treatment with panitumumab.
This is the first time that a missense mutation of the target of a therapeutic antibody has been reported as cause of resistance to that antibody. It could help deciding which patients who have become resistant to treatment with cetuximab could still benefit from using panitumumab.
Montagut C, Dalmases A, Bellosillo B, Crespo M, Pairet S, Iglesias M, Salido M, Gallen M, Marsters S, Tsai SP, Minoche A, Somasekar S, Serrano S, Himmelbauer H, Bellmunt J, Rovira A, Settleman J, Bosch F, Albanell J. Identification of a mutation in the extracellular domain of the Epidermal Growth Factor Receptor conferring cetuximab resistance in colorectal cancer. Nat Med. 2012 Jan 22;
Analysing the Colon crypts
This image of a transversal cut of the colon shows the intestinal crypts stained with haematoxylin and eosin. The aim was to detect the presence of the activated IKK alpha protein (in brown). In healthy intestinal crypts such as those in the image, most of the cells are negative for this staining and the only brown cells are the lymphocytes that occupy the spaces in between the crypts. In colon tumour samples, on the other hand, there are high levels of activated IKK alpha in the cells of the crypt.