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Some lung cancers escape a targeted pill without changing the target at all: they simply make many extra copies of a second receptor that switches the same growth signal back on.
A gefitinib-sensitive lung cancer cell line that developed resistance was found to carry focal amplification of the MET proto-oncogene, and inhibiting MET signalling restored sensitivity. MET amplification was detected in 4 of 18 lung cancer specimens, 22%, that had developed resistance to gefitinib or erlotinib. Amplification of MET causes resistance by driving ERBB3-dependent activation of PI3K, a pathway previously thought to be specific to the EGFR and ERBB receptor family, so MET amplification may promote drug resistance in other ERBB-driven cancers as well.
It defined bypass resistance as a category and set the treatment rule that follows from it: keep blocking the original target and add an inhibitor of the bypass, which is the logic of every EGFR plus MET combination since.
Shares MET amplification (gene copy number), MET amplification (bypass resistance), Gefitinib, Erlotinib.
Shares MET amplification (gene copy number), Pasi A. Jänne, MET amplification (bypass resistance), Gene amplification and copy-number change.
Shares Gefitinib, Erlotinib, Resistance routes: how a blocked pathway comes back, Drug resistance (primary and acquired).
Shares MET amplification (gene copy number), MET amplification (bypass resistance), Resistance routes: how a blocked pathway comes back, MET.
Shares Pasi A. Jänne, Resistance routes: how a blocked pathway comes back, MET, Drug resistance (primary and acquired).
Shares Pasi A. Jänne, Gefitinib, Resistance routes: how a blocked pathway comes back, Drug resistance (primary and acquired).
Shares Gefitinib, Erlotinib, Massachusetts General Hospital Cancer Center, MET.
Shares Pasi A. Jänne, Gefitinib, Science, Dana-Farber Brigham Cancer Center.