{"entity":{"id":"gatekeeper-mutation","kind":"term","name":"On-target resistance mutations (gatekeeper, solvent-front, compound)","aka":["gatekeeper","gatekeeper mutation","solvent-front mutation","solvent front","compound mutations","compound mutation","G1202R","G2032R","on-target resistance","secondary mutation","resistance mutation","acquired resistance mutation","kinase domain mutation","resistance mutations","gatekeeper mutations","secondary mutations","solvent-front mutations"],"tldr":"When a cancer becomes resistant to a targeted pill, it often does so by changing the exact spot where the drug binds: a 'gatekeeper' or 'solvent-front' mutation. Next-generation drugs are designed to fit around these changes.","summary":"Gatekeeper mutations (EGFR T790M, ABL T315I, KIT T670I) alter a residue at the entrance to the ATP pocket; solvent-front mutations (ALK G1202R, ROS1 G2032R, NTRK G595R) change the drug's contact surface; compound mutations stack two or more changes and defeat successive drug generations. Each generation of inhibitor answers the last: osimertinib for T790M, lorlatinib and neladalkib for G1202R, ponatinib and asciminib for T315I, repotrectinib for G2032R. Re-biopsy or ctDNA at progression identifies the mutation and guides the switch; off-target bypass (MET amplification, histologic transformation) is the other main route.","asOf":"2026-09-09","wikipedia":"https://en.wikipedia.org/wiki/Drug_resistance","links":[{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/Drug_resistance"}],"tags":[],"related":["resistance","egfr-mutation-subtypes","tki-term","cfdna"],"cancers":[],"sections":["targeted-therapy"],"technologies":[],"targets":["egfr","alk","ros1"],"drugs":["osimertinib","ponatinib","asciminib"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"category":"Biomarkers"},"route":"/terms/gatekeeper-mutation/","neighbours":{"term":[{"id":"abl1-kinase-domain-mutations","kind":"term","name":"BCR::ABL1 kinase domain mutations (T315I and others)","route":"/terms/abl1-kinase-domain-mutations/"},{"id":"btki-bcl2i-resistance-mutations","kind":"term","name":"BTK C481S, PLCG2 and BCL2 G101V resistance mutations","route":"/terms/btki-bcl2i-resistance-mutations/"},{"id":"cfdna","kind":"term","name":"Cell-free DNA (cfDNA)","route":"/terms/cfdna/"},{"id":"resistance","kind":"term","name":"Drug resistance (primary and acquired)","route":"/terms/resistance/"},{"id":"egfr-mutation-subtypes","kind":"term","name":"EGFR mutation subtypes (exon 19 deletion, L858R, exon 20 insertion, T790M)","route":"/terms/egfr-mutation-subtypes/"},{"id":"met-exon-14-skipping","kind":"term","name":"MET exon 14 skipping mutation","route":"/terms/met-exon-14-skipping/"},{"id":"tki-term","kind":"term","name":"Tyrosine kinase inhibitor (TKI)","route":"/terms/tki-term/"}],"section":[{"id":"targeted-therapy","kind":"section","name":"Targeted Therapy","route":"/fronts/targeted-therapy/"}],"target":[{"id":"alk","kind":"target","name":"ALK","route":"/targets/alk/"},{"id":"egfr","kind":"target","name":"EGFR","route":"/targets/egfr/"},{"id":"ros1","kind":"target","name":"ROS1","route":"/targets/ros1/"}],"drug":[{"id":"asciminib","kind":"drug","name":"Asciminib","route":"/drugs/asciminib/"},{"id":"osimertinib","kind":"drug","name":"Osimertinib","route":"/drugs/osimertinib/"},{"id":"ponatinib","kind":"drug","name":"Ponatinib","route":"/drugs/ponatinib/"}],"trial":[{"id":"aura3","kind":"trial","name":"AURA3","route":"/trials/aura3/"}],"biomarker":[{"id":"bcr-abl1-t315i","kind":"biomarker","name":"BCR::ABL1 T315I","route":"/biomarkers/bcr-abl1-t315i/"},{"id":"egfr-t790m","kind":"biomarker","name":"EGFR T790M","route":"/biomarkers/egfr-t790m/"},{"id":"flt3-tkd","kind":"biomarker","name":"FLT3-TKD (D835 and I836 tyrosine kinase domain mutations)","route":"/biomarkers/flt3-tkd/"},{"id":"kit-d816v","kind":"biomarker","name":"KIT D816V","route":"/biomarkers/kit-d816v/"}],"cancer":[{"id":"alk-positive-nsclc","kind":"cancer","name":"ALK-positive non-small-cell lung cancer","route":"/cancers/alk-positive-nsclc/"},{"id":"lung-cancer","kind":"cancer","name":"Lung cancer (all types)","route":"/cancers/lung-cancer/"},{"id":"ntrk-fusion-nsclc","kind":"cancer","name":"NTRK fusion-positive non-small-cell lung cancer","route":"/cancers/ntrk-fusion-nsclc/"},{"id":"ret-fusion-nsclc","kind":"cancer","name":"RET fusion-positive non-small-cell lung cancer","route":"/cancers/ret-fusion-nsclc/"},{"id":"ros1-positive-nsclc","kind":"cancer","name":"ROS1-positive non-small-cell lung cancer","route":"/cancers/ros1-positive-nsclc/"}]}}