# On-target resistance mutations (gatekeeper, solvent-front, compound)

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

## TL;DR

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.

## Fields

- Kind: Term
- Last checked: 2026-09-09
- Also known as: 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

## Sources

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

## Connected records

- terms: [BCR::ABL1 kinase domain mutations (T315I and others)](https://onco.cc/terms/abl1-kinase-domain-mutations/), [BTK C481S, PLCG2 and BCL2 G101V resistance mutations](https://onco.cc/terms/btki-bcl2i-resistance-mutations/), [Cell-free DNA (cfDNA)](https://onco.cc/terms/cfdna/), [Drug resistance (primary and acquired)](https://onco.cc/terms/resistance/), [EGFR mutation subtypes (exon 19 deletion, L858R, exon 20 insertion, T790M)](https://onco.cc/terms/egfr-mutation-subtypes/), [MET exon 14 skipping mutation](https://onco.cc/terms/met-exon-14-skipping/), [Tyrosine kinase inhibitor (TKI)](https://onco.cc/terms/tki-term/)
- fronts: [Targeted Therapy](https://onco.cc/fronts/targeted-therapy/)
- targets: [ALK](https://onco.cc/targets/alk/), [EGFR](https://onco.cc/targets/egfr/), [ROS1](https://onco.cc/targets/ros1/)
- drugs: [Asciminib](https://onco.cc/drugs/asciminib/), [Osimertinib](https://onco.cc/drugs/osimertinib/), [Ponatinib](https://onco.cc/drugs/ponatinib/)
- trials: [AURA3](https://onco.cc/trials/aura3/)
- biomarkers: [BCR::ABL1 T315I](https://onco.cc/biomarkers/bcr-abl1-t315i/), [EGFR T790M](https://onco.cc/biomarkers/egfr-t790m/), [FLT3-TKD (D835 and I836 tyrosine kinase domain mutations)](https://onco.cc/biomarkers/flt3-tkd/), [KIT D816V](https://onco.cc/biomarkers/kit-d816v/)
- cancers: [ALK-positive non-small-cell lung cancer](https://onco.cc/cancers/alk-positive-nsclc/), [Lung cancer (all types)](https://onco.cc/cancers/lung-cancer/), [NTRK fusion-positive non-small-cell lung cancer](https://onco.cc/cancers/ntrk-fusion-nsclc/), [RET fusion-positive non-small-cell lung cancer](https://onco.cc/cancers/ret-fusion-nsclc/), [ROS1-positive non-small-cell lung cancer](https://onco.cc/cancers/ros1-positive-nsclc/)

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JSON: https://onco.cc/api/v1/entities/gatekeeper-mutation.json