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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), EGFR, KRAS.
Shares Panitumumab, Circulating tumour DNA (ctDNA), EGFR, KRAS.
Shares Kenneth W. Kinzler, Bert Vogelstein, Cell-free DNA (cfDNA), Johns Hopkins Hospital / Sidney Kimmel Comprehensive Cancer Center.