{"entity":{"id":"downstream","kind":"term","name":"Downstream and upstream","aka":["downstream","upstream","downstream of","upstream of","downstream signalling","downstream signaling","downstream effector","downstream effectors","downstream target","downstream targets"],"tldr":"Position in a signalling chain: upstream proteins send the message, downstream proteins receive it. A mutation downstream of a drug's target can make the drug useless.","summary":"In the RAS-MAPK pathway, the EGFR receptor is upstream of RAS, which is upstream of RAF, MEK and ERK; the nucleus is the far downstream end. The direction matters for treatment because blocking an upstream protein does nothing if a downstream one is already stuck on: EGFR antibodies fail in colorectal cancers with KRAS mutations because KRAS sits below EGFR and fires regardless. The same logic explains why resistance so often emerges downstream of a drug target and why combination therapy sometimes pairs an upstream and a downstream inhibitor.","asOf":"2026-09-09","wikipedia":"https://en.wikipedia.org/wiki/Signal_transduction","links":[{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/Signal_transduction"}],"tags":[],"related":["signalling-pathway","growth-signal","kinase","resistance"],"cancers":[],"sections":[],"technologies":[],"targets":["egfr","kras","braf"],"drugs":[],"companies":[],"institutions":[],"pathways":["ras-mapk","pi3k-akt-mtor"],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"category":"Biology basics"},"route":"/terms/downstream/","neighbours":{"term":[{"id":"resistance","kind":"term","name":"Drug resistance (primary and acquired)","route":"/terms/resistance/"},{"id":"growth-signal","kind":"term","name":"Growth signal","route":"/terms/growth-signal/"},{"id":"kinase","kind":"term","name":"Kinase","route":"/terms/kinase/"},{"id":"signalling-pathway","kind":"term","name":"Signalling pathway","route":"/terms/signalling-pathway/"}],"target":[{"id":"braf","kind":"target","name":"BRAF","route":"/targets/braf/"},{"id":"egfr","kind":"target","name":"EGFR","route":"/targets/egfr/"},{"id":"kras","kind":"target","name":"KRAS","route":"/targets/kras/"}],"pathway":[{"id":"pi3k-akt-mtor","kind":"pathway","name":"PI3K / AKT / mTOR","route":"/pathways/pi3k-akt-mtor/"},{"id":"ras-mapk","kind":"pathway","name":"RAS / RAF / MEK / ERK (MAPK)","route":"/pathways/ras-mapk/"}]}}