Journal Article

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

Williams, Richard T., Wu, Jian, Hecht, J. Randolph, Bozic, Ivana, Oliner, Kelly S., Berlin, Jordan, Vogelstein, Bert, Reiter, Johannes G., Kinzler, Kenneth W., Kinde, Isaac, Nowak, Martin A., Diaz Jr, Luis A., Allen, Benjamin

2012

Overview

This work on colorectal cancer shows that secondary mutations in KRAS that confer resistance to panitumumab, an anti-EGFR monoclonal antibody, are already present when antibody treatment begins; the apparent inevitability of resistance suggests that combinations of drugs targeting at least two different oncogenic pathway will be needed for treatment. Acquired resistance in anti-EGFR therapy Antibodies targeting epidermal growth factor receptor (EGFR) have become an established treatment for colorectal cancer, but they are contraindicated in patients carrying mutations in the KRAS oncogene. Drug resistance can also arise in initially responsive patients, and two papers in this issue of Nature present unequivocal evidence that mutations in KRAS underlie acquired resistance to anti-EGFR antibodies in many patients and that KRAS mutations can be detected in the serum of patients before the clinical emergence of resistance and relapse. Misale et al . show in cell-line models that KRAS mutations can confer resistance to cetuximab. And in colorectal cancer patients treated with cetuximab or panitumumab, resistance is associated with KRAS mutations selected from pre-existing subclones or acquired during treatment. Diaz et al . also find KRAS mutations accumulating in patients becoming resistant to panitumumab. Their mathematical models suggest that KRAS mutations pre-existed in tumour cells before therapy, which may explain why clinical recurrence is usually seen after about six months of treatment, by which time the resistant subpopulations of tumour cells with KRAS mutations has expanded. The apparent inevitability of resistance suggests that combinations of drugs targeting more than one oncogenic pathway will be needed if resistance is to be avoided. Colorectal tumours that are wild type for KRAS are often sensitive to EGFR blockade, but almost always develop resistance within several months of initiating therapy 1 , 2 . The mechanisms underlying this acquired resistance to anti-EGFR antibodies are largely unknown. This situation is in marked contrast to that of small-molecule targeted agents, such as inhibitors of ABL, EGFR, BRAF and MEK, in which mutations in the genes encoding the protein targets render the tumours resistant to the effects of the drugs 3 , 4 , 5 , 6 . The simplest hypothesis to account for the development of resistance to EGFR blockade is that rare cells with KRAS mutations pre-exist at low levels in tumours with ostensibly wild-type KRAS genes. Although this hypothesis would seem readily testable, there is no evidence in pre-clinical models to support it, nor is there data from patients. To test this hypothesis, we determined whether mutant KRAS DNA could be detected in the circulation of 28 patients receiving monotherapy with panitumumab, a therapeutic anti-EGFR antibody. We found that 9 out of 24 (38%) patients whose tumours were initially KRAS wild type developed detectable mutations in KRAS in their sera, three of which developed multiple different KRAS mutations. The appearance of these mutations was very consistent, generally occurring between 5 and 6 months following treatment. Mathematical modelling indicated that the mutations were present in expanded subclones before the initiation of panitumumab treatment. These results suggest that the emergence of KRAS mutations is a mediator of acquired resistance to EGFR blockade and that these mutations can be detected in a non-invasive manner. They explain why solid tumours develop resistance to targeted therapies in a highly reproducible fashion.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 631/208/212/2304 / 631/67/1059/2326 / 631/67/1504/1885 / Antibodies, Monoclonal - pharmacology / Antibodies, Monoclonal - therapeutic use / Biological and medical sciences / Cell division / Cell physiology / Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes / Colorectal cancer / Colorectal Neoplasms - blood / Colorectal Neoplasms - drug therapy / Colorectal Neoplasms - genetics / Colorectal Neoplasms - pathology / Confidence intervals / DNA, Neoplasm - blood / Drug Resistance, Neoplasm - drug effects / Drug Resistance, Neoplasm - genetics / Drug therapy / ErbB Receptors - antagonists & inhibitors / Evolution, Molecular / Fundamental and applied biological sciences. Psychology / Genes, ras - genetics / Growth rate / Humanities and Social Sciences / Humans / Hypotheses / letter / Molecular and cellular biology / multidisciplinary / Mutation / Mutation - genetics / Panitumumab / Proto-Oncogene Proteins - genetics / Proto-Oncogene Proteins p21(ras) / ras Proteins - genetics / Science / Science (multidisciplinary) / Selection, Genetic - drug effects / Standard deviation / Time Factors / Tumors