# Downstream and upstream

Source: https://onco.cc/terms/downstream/  
OnCo record `downstream` (Term). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

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.

## Fields

- Kind: Term
- Last checked: 2026-09-09
- Also known as: downstream; upstream; downstream of; upstream of; downstream signalling; downstream signaling; downstream effector; downstream effectors; downstream target; downstream targets

## Sources

- Wikipedia: https://en.wikipedia.org/wiki/Signal_transduction
- Wikipedia: https://en.wikipedia.org/wiki/Signal_transduction

## Connected records

- terms: [Drug resistance (primary and acquired)](https://onco.cc/terms/resistance/), [Growth signal](https://onco.cc/terms/growth-signal/), [Kinase](https://onco.cc/terms/kinase/), [Signalling pathway](https://onco.cc/terms/signalling-pathway/)
- targets: [BRAF](https://onco.cc/targets/braf/), [EGFR](https://onco.cc/targets/egfr/), [KRAS](https://onco.cc/targets/kras/)
- pathways: [PI3K / AKT / mTOR](https://onco.cc/pathways/pi3k-akt-mtor/), [RAS / RAF / MEK / ERK (MAPK)](https://onco.cc/pathways/ras-mapk/)

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JSON: https://onco.cc/api/v1/entities/downstream.json