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Published beside the paper above: resistance to EGFR antibodies does not have to be invented, it is already there. Rare KRAS-mutant cells present before treatment expand under it, on a schedule a mathematical model predicts.
The hypothesis that rare cells with KRAS mutations pre-exist at low levels in tumours with ostensibly wild-type KRAS genes was tested by looking for mutant KRAS DNA in the circulation of 28 patients receiving monotherapy with panitumumab. Of 24 patients whose tumours were initially KRAS wild-type, 9 (38%) developed detectable KRAS mutations in their serum, three of them multiple different mutations. The appearance of the mutations was consistent, generally occurring between 5 and 6 months after starting treatment. Mathematical modelling indicated that the mutations were present in expanded subclones before panitumumab was begun, explaining why solid tumours develop resistance to targeted therapies in a highly reproducible fashion.
It reframed resistance as selection rather than mutation, which is why the field now asks how to suppress a pre-existing clone rather than how to prevent a new mutation, and why ctDNA is the natural monitoring tool.
Shares Panitumumab, Cell-free DNA (cfDNA), Clonal evolution & minimal residual disease, Nature.
Shares Kenneth W. Kinzler, Bert Vogelstein, Clonal evolution & minimal residual disease, Nature.
Shares Kenneth W. Kinzler, Bert Vogelstein, Nature, Johns Hopkins Hospital / Sidney Kimmel Comprehensive Cancer Center.
Shares Kenneth W. Kinzler, Bert Vogelstein, Cell-free DNA (cfDNA), Johns Hopkins Hospital / Sidney Kimmel Comprehensive Cancer Center.
Shares Bert Vogelstein, Cell-free DNA (cfDNA), Johns Hopkins Hospital / Sidney Kimmel Comprehensive Cancer Center, Circulating tumour DNA (ctDNA).
Shares Panitumumab, Circulating tumour DNA (ctDNA), KRAS, EGFR.
Shares Panitumumab, Circulating tumour DNA (ctDNA), KRAS, EGFR.
Shares Guardant360 CDx, Cell-free DNA (cfDNA), Circulating tumour DNA (ctDNA), KRAS.
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