The molecular evolution of acquired resistance to targeted EGFR blockade in colorectal cancers.
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.
Ludwig Center for Cancer Genetics and Therapeutics, Howard Hughes Medical Institute at Johns Hopkins Kimmel Cancer Center, Baltimore, Maryland 21287, USA. ldiaz1@jhmi.edu
Luis A
LA
Diaz
Richard T
RT
Williams
Jian
J
Wu
Isaac
I
Kinde
J Randolph
JR
Hecht
Jordan
J
Berlin
Benjamin
B
Allen
Ivana
I
Bozic
Johannes G
JG
Reiter
Martin A
MA
Nowak
Kenneth W
KW
Kinzler
Kelly S
KS
Oliner
Bert
B
Vogelstein
D000911:Antibodies, Monoclonal / Q000494:pharmacology* / Q000627:therapeutic use; D015179:Colorectal Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D004273:DNA, Neoplasm / Q000097:blood; D019008:Drug Resistance, Neoplasm / Q000187:drug effects* / Q000235:genetics; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D019143:Evolution, Molecular; D011905:Genes, ras / Q000235:genetics; D006801:Humans; D009154:Mutation / Q000235:genetics; D000077544:Panitumumab; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D016283:Proto-Oncogene Proteins p21(ras); D012641:Selection, Genetic / Q000187:drug effects; D013997:Time Factors; D018631:ras Proteins / Q000235:genetics*
D000911:Antibodies, Monoclonal; D004273:DNA, Neoplasm; C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; D000077544:Panitumumab; D066246:ErbB Receptors; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins