Publication Date:
2012-06-23
Description:
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. 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. 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.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3436069/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3436069/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Diaz, Luis A Jr -- Williams, Richard T -- Wu, Jian -- Kinde, Isaac -- Hecht, J Randolph -- Berlin, Jordan -- Allen, Benjamin -- Bozic, Ivana -- Reiter, Johannes G -- Nowak, Martin A -- Kinzler, Kenneth W -- Oliner, Kelly S -- Vogelstein, Bert -- CA095103/CA/NCI NIH HHS/ -- CA129825/CA/NCI NIH HHS/ -- CA43460/CA/NCI NIH HHS/ -- CA57345/CA/NCI NIH HHS/ -- CA62924/CA/NCI NIH HHS/ -- N01-CN-43309/CN/NCI NIH HHS/ -- P50 CA095103/CA/NCI NIH HHS/ -- R01 GM058008/GM/NIGMS NIH HHS/ -- R01GM078986/GM/NIGMS NIH HHS/ -- R37 CA043460/CA/NCI NIH HHS/ -- R37 CA057345/CA/NCI NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2012 Jun 28;486(7404):537-40. doi: 10.1038/nature11219.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Ludwig Center for Cancer Genetics and Therapeutics, Howard Hughes Medical Institute at Johns Hopkins Kimmel Cancer Center, Baltimore, Maryland 21287, USA. ldiaz1@jhmi.edu〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22722843" target="_blank"〉PubMed〈/a〉
Keywords:
Antibodies, Monoclonal/*pharmacology/therapeutic use
;
Colorectal Neoplasms/blood/*drug therapy/*genetics/pathology
;
DNA, Neoplasm/blood
;
Drug Resistance, Neoplasm/*drug effects/genetics
;
*Evolution, Molecular
;
Genes, ras/genetics
;
Humans
;
Mutation/genetics
;
Proto-Oncogene Proteins/*genetics
;
Receptor, Epidermal Growth Factor/*antagonists & inhibitors
;
Selection, Genetic/drug effects
;
Time Factors
;
ras Proteins/*genetics
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
