# Receptor tyrosine kinase activation

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

## TL;DR

Growth-factor receptors are antennas on the cell surface that pair up when a signal lands and switch on the growth relays inside. Cancers mutate, multiply, or fuse these antennas so they broadcast 'grow' with no signal at all. Most targeted drugs, antibodies and ADCs start here.

## Summary

Ligand binding (EGF, HGF, FGF, NRG, SCF, PDGF, VEGF) dimerises RTKs, trans-autophosphorylating tyrosines that recruit SH2/PTB adaptors: GRB2-SOS to RAS-MAPK, p85 to PI3K-AKT, PLCγ, SRC, STAT3/5, and CBL for ubiquitin-mediated downregulation. Oncogenic activation: kinase-domain mutations (EGFR L858R/exon 19, exon 20 insertions; FLT3-ITD; KIT exon 11; HER2), extracellular-domain truncation (EGFRvIII), amplification (HER2, MET, FGFR1/2), fusions (ALK, ROS1, RET, NTRK, FGFR2/3, with dimerisation domains that pair the kinase constitutively), autocrine loops, and PTPN11 or CBL loss. Drug classes: reversible and covalent TKIs (with resistance via gatekeeper/solvent-front mutations such as EGFR C797S, ALK G1202R), antibodies that block ligand or receptor and recruit Fc effectors (trastuzumab, cetuximab), bispecifics (amivantamab EGFR×MET, zanidatamab HER2×HER2), and ADCs that use the receptor as a delivery address regardless of signalling (T-DXd on HER2-low). Bypass via a parallel RTK (MET amplification under EGFR blockade, HER3 upregulation) is the classic escape.

## Fields

- Kind: Pathway
- Last checked: 2026-09-09
- Tags: mechanism; mechanics-atlas
- Analogy: Two halves of a walkie-talkie that only transmit when clipped together by a signal from outside. Cancer glues them together (fusions, mutations) or installs hundreds of extra sets (amplification), so the room is full of shouted 'grow' orders. TKIs pull the battery, antibodies tape over the microphone, ADCs use the aerial as a mailing address for poison.
- Interventions: TKIs by driver: osimertinib (EGFR), lorlatinib/alectinib (ALK), selpercatinib (RET), larotrectinib/entrectinib (NTRK), capmatinib/tepotinib (MET), imatinib (KIT/PDGFRA/BCR-ABL), zongertinib (HER2); Antibodies: trastuzumab/pertuzumab (HER2), cetuximab/panitumumab (EGFR); bispecifics amivantamab (EGFR×MET), zanidatamab, zenocutuzumab (HER2×HER3); ADCs use the receptor as an address: T-DXd, T-DM1, patritumab deruxtecan (HER3), telisotuzumab vedotin (MET); Combining with MET or downstream inhibitors closes bypass routes

## Sources

- Wikipedia: https://en.wikipedia.org/wiki/Receptor_tyrosine_kinase
- Lemmon & Schlessinger, Cell signaling by receptor tyrosine kinases (Cell 2010): https://doi.org/10.1016/j.cell.2010.06.011

## Connected records

- cancers: [ALK-positive non-small-cell lung cancer](https://onco.cc/cancers/alk-positive-nsclc/), [Biliary tract cancer (cholangiocarcinoma)](https://onco.cc/cancers/cholangiocarcinoma/), [Colorectal cancer](https://onco.cc/cancers/colorectal/), [EGFR-mutated non-small-cell lung cancer](https://onco.cc/cancers/egfr-mutant-nsclc/), [Gallbladder cancer](https://onco.cc/cancers/gallbladder/), [Gastric & gastro-oesophageal junction cancer](https://onco.cc/cancers/gastric/), [Gastrointestinal stromal tumour (GIST)](https://onco.cc/cancers/gist/), [HER2-mutant non-small-cell lung cancer](https://onco.cc/cancers/her2-mutant-nsclc/), [HER2-positive breast cancer](https://onco.cc/cancers/breast-her2-positive/), [Inflammatory myofibroblastic tumour (IMT)](https://onco.cc/cancers/inflammatory-myofibroblastic-tumour/), [KRAS G12C-mutant pancreatic ductal adenocarcinoma](https://onco.cc/cancers/kras-g12c-pdac/), [KRAS wild-type pancreatic ductal adenocarcinoma](https://onco.cc/cancers/kras-wild-type-pdac/), [MET exon 14 and MET-amplified non-small-cell lung cancer](https://onco.cc/cancers/met-altered-nsclc/), [Multiple endocrine neoplasia syndromes (MEN1, MEN2, MEN4)](https://onco.cc/cancers/multiple-endocrine-neoplasia/), [Non-small-cell lung cancer](https://onco.cc/cancers/nsclc/), [NTRK fusion-positive non-small-cell lung cancer](https://onco.cc/cancers/ntrk-fusion-nsclc/), [Pancreatic ductal adenocarcinoma](https://onco.cc/cancers/pancreatic/), [Pheochromocytoma and paraganglioma (PPGL)](https://onco.cc/cancers/pheochromocytoma-paraganglioma/), [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/), [Systemic mastocytosis](https://onco.cc/cancers/systemic-mastocytosis/), [Thyroid cancer](https://onco.cc/cancers/thyroid/), [Triple-negative breast cancer (TNBC)](https://onco.cc/cancers/tnbc/)
- technologies: [Antibody-drug conjugate (ADC)](https://onco.cc/technologies/adc/), [Bispecific antibodies](https://onco.cc/technologies/bispecific-antibody/), [Companion diagnostics](https://onco.cc/technologies/companion-diagnostic/), [Monoclonal antibodies](https://onco.cc/technologies/monoclonal-antibody/), [Small-molecule kinase inhibitors](https://onco.cc/technologies/kinase-inhibitors/)
- targets: [ALK](https://onco.cc/targets/alk/), [CBL](https://onco.cc/targets/cbl/), [EGF](https://onco.cc/targets/egf/), [EGFR](https://onco.cc/targets/egfr/), [FGFR2](https://onco.cc/targets/fgfr2/), [FLT3](https://onco.cc/targets/flt3/), [GRB2](https://onco.cc/targets/grb2/), [HER2](https://onco.cc/targets/her2/), [HER3](https://onco.cc/targets/her3/), [HGF](https://onco.cc/targets/hgf/), [KIT](https://onco.cc/targets/kit/), [KRAS](https://onco.cc/targets/kras/), [MET](https://onco.cc/targets/met/), [NTRK](https://onco.cc/targets/ntrk/), [PDGFRA](https://onco.cc/targets/pdgfra/), [PIK3CA / PI3K-alpha](https://onco.cc/targets/pik3ca/), [RET](https://onco.cc/targets/ret/), [ROS1](https://onco.cc/targets/ros1/), [SHP2 (PTPN11)](https://onco.cc/targets/shp2/), [STAT3](https://onco.cc/targets/stat3/)
- drugs: [Alectinib](https://onco.cc/drugs/alectinib/), [Amivantamab](https://onco.cc/drugs/amivantamab/), [Capmatinib & tepotinib](https://onco.cc/drugs/capmatinib-tepotinib/), [Cetuximab](https://onco.cc/drugs/cetuximab/), [Entrectinib](https://onco.cc/drugs/entrectinib/), [Imatinib](https://onco.cc/drugs/imatinib/), [Larotrectinib](https://onco.cc/drugs/larotrectinib/), [Lorlatinib](https://onco.cc/drugs/lorlatinib/), [Osimertinib](https://onco.cc/drugs/osimertinib/), [Panitumumab](https://onco.cc/drugs/panitumumab/), [Patritumab deruxtecan](https://onco.cc/drugs/patritumab-deruxtecan/), [Pertuzumab](https://onco.cc/drugs/pertuzumab/), [Selpercatinib](https://onco.cc/drugs/selpercatinib/), [Telisotuzumab vedotin](https://onco.cc/drugs/telisotuzumab-vedotin/), [Trastuzumab](https://onco.cc/drugs/trastuzumab/), [Trastuzumab deruxtecan](https://onco.cc/drugs/trastuzumab-deruxtecan/), [Zanidatamab](https://onco.cc/drugs/zanidatamab/), [Zenocutuzumab](https://onco.cc/drugs/zenocutuzumab/), [Zongertinib](https://onco.cc/drugs/zongertinib/)
- pathways: [Acute myeloid leukaemia (KEGG map)](https://onco.cc/pathways/aml-signalling/), [Breast cancer (KEGG map)](https://onco.cc/pathways/breast-cancer-signalling/), [Gastric cancer (KEGG map)](https://onco.cc/pathways/gastric-cancer-signalling/), [Glioma (KEGG map)](https://onco.cc/pathways/glioma-signalling/), [Hepatocellular carcinoma (KEGG map)](https://onco.cc/pathways/hepatocellular-carcinoma-signalling/), [JAK-STAT signalling](https://onco.cc/pathways/jak-stat/), [Non-small cell lung cancer (KEGG map)](https://onco.cc/pathways/nsclc-signalling/), [Pancreatic cancer (KEGG map)](https://onco.cc/pathways/pancreatic-cancer-signalling/), [PI3K / AKT / mTOR](https://onco.cc/pathways/pi3k-akt-mtor/), [Prostate cancer (KEGG map)](https://onco.cc/pathways/prostate-cancer-signalling/), [Proteoglycans in cancer](https://onco.cc/pathways/proteoglycans-in-cancer/), [RAS / RAF / MEK / ERK (MAPK)](https://onco.cc/pathways/ras-mapk/), [Renal cell carcinoma (KEGG map)](https://onco.cc/pathways/renal-cell-carcinoma-signalling/), [Resistance routes: how a blocked pathway comes back](https://onco.cc/pathways/resistance-routes-map/), [Thyroid cancer (KEGG map)](https://onco.cc/pathways/thyroid-cancer-signalling/)
- terms: [ADCC (antibody-dependent cellular cytotoxicity)](https://onco.cc/terms/adcc/), [EGFR C797S](https://onco.cc/terms/c797s/), [EGFR exon 19 deletion & L858R](https://onco.cc/terms/egfr-exon19-l858r/), [EGFR exon 20 insertion](https://onco.cc/terms/egfr-exon20-insertion/), [EGFRvIII](https://onco.cc/terms/egfrviii/), [Gene fusion](https://onco.cc/terms/gene-fusion/), [HER2-low and HER2-ultralow](https://onco.cc/terms/her2-low/), [MET amplification (bypass resistance)](https://onco.cc/terms/met-amplification/), [Oncogene addiction](https://onco.cc/terms/oncogene-addiction/)
- key papers: [A molecularly annotated platform of patient-derived xenografts identifies HER2 as an effective therapeutic target in cetuximab-resistant colorectal cancer](https://onco.cc/key-papers/paper-bertotti-xenopatients-her2-cetuximab-resistant-colorectal-cancer-discov-2011/), [Acquired EGFR C797S mutation mediates resistance to AZD9291 in non-small cell lung cancer harboring EGFR T790M](https://onco.cc/key-papers/paper-thress-nat-med/), [Acquired resistance of lung adenocarcinomas to gefitinib or erlotinib is associated with a second mutation in the EGFR kinase domain](https://onco.cc/key-papers/paper-pao-egfr-t790m-acquired-resistance-plos-med-2005/), [ALK resistance mutations and efficacy of lorlatinib in advanced anaplastic lymphoma kinase-positive non-small-cell lung cancer](https://onco.cc/key-papers/paper-shaw-alk-resistance-mutations-lorlatinib-jco-2019/), [Analysis of tumor specimens at the time of acquired resistance to EGFR-TKI therapy in 155 patients with EGFR-mutant lung cancers](https://onco.cc/key-papers/paper-yu-acquired-resistance-rebiopsy-egfr-ccr-2013/), [Assessment of resistance mechanisms and clinical implications in patients with EGFR T790M-positive lung cancer and acquired resistance to osimertinib](https://onco.cc/key-papers/paper-oxnard-osimertinib-resistance-mechanisms-jama-oncol-2018/), [CD74-NRG1 fusions in lung adenocarcinoma](https://onco.cc/key-papers/paper-fernandez-cuesta-cd74-nrg1-fusion-lung-cancer-discov-2014/), [Circulating tumor DNA-guided treatment with pertuzumab plus trastuzumab for HER2-amplified metastatic colorectal cancer: a phase 2 trial (TRIUMPH)](https://onco.cc/key-papers/paper-nakamura-triumph-ctdna-pertuzumab-trastuzumab-her2-colorectal-nat-med-2021/), [Clinical implications of plasma-based genotyping with the delivery of personalized therapy in metastatic non-small cell lung cancer](https://onco.cc/key-papers/paper-aggarwal-plasma-genotyping-personalised-therapy-jama-oncol-2019/), [Comprehensive molecular profiling of lung adenocarcinoma](https://onco.cc/key-papers/paper-tcga-lung-adenocarcinoma-nature-2014/), [Detection of NRG1 gene fusions in solid tumors](https://onco.cc/key-papers/paper-jonna-nrg1-fusions-solid-tumours-ccr-2019/), [Dual-targeted therapy with trastuzumab and lapatinib in treatment-refractory, KRAS codon 12/13 wild-type, HER2-positive metastatic colorectal cancer (HERACLES)](https://onco.cc/key-papers/paper-sartore-bianchi-heracles-trastuzumab-lapatinib-lancet-oncol-2016/), [EGFR mutation and resistance of non-small-cell lung cancer to gefitinib](https://onco.cc/key-papers/paper-kobayashi-egfr-t790m-gefitinib-resistance-nejm-2005/), [eNRGy: efficacy of zenocutuzumab in NRG1 fusion-positive cancer](https://onco.cc/key-papers/paper-enrgy-zenocutuzumab-nrg1-fusion-positive-cancer-nejm-2025/), [Frequent and focal FGFR1 amplification associates with therapeutically tractable FGFR1 dependency in squamous cell lung cancer](https://onco.cc/key-papers/paper-weiss-fgfr1-amplification-squamous-lung-sci-transl-med-2010/), [Genomic and evolutionary classification of lung cancer in never smokers](https://onco.cc/key-papers/paper-zhang-lung-cancer-never-smokers-nat-genet-2021/), [Genomic landscape of lung adenocarcinoma in East Asians](https://onco.cc/key-papers/paper-chen-east-asian-lung-adenocarcinoma-nat-genet-2020/), [Heining 2018: NRG1 fusions in KRAS wild-type pancreatic cancer](https://onco.cc/key-papers/paper-heining-nrg1-fusions-kras-wild-type-pancreatic-cancer-discov-2018/), [Identification of targetable ALK rearrangements in pancreatic ductal adenocarcinoma](https://onco.cc/key-papers/paper-singhi-alk-rearrangements-pancreatic-jnccn-2017/), [Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer](https://onco.cc/key-papers/paper-soda-eml4-alk-fusion-nature-2007/), [Jones 2019: NRG1 gene fusions are recurrent, clinically actionable rearrangements in KRAS wild-type pancreatic ductal adenocarcinoma](https://onco.cc/key-papers/paper-jones-nrg1-fusions-recurrent-actionable-kras-wild-type-pdac-ccr-2019/), [Lemmon and Schlessinger 2010: cell signalling by receptor tyrosine kinases](https://onco.cc/key-papers/paper-lemmon-schlessinger-rtk-signalling-cell-2010/), [MET amplification leads to gefitinib resistance in lung cancer by activating ERBB3 signaling](https://onco.cc/key-papers/paper-engelman-met-amplification-gefitinib-resistance-science-2007/), [MET exon 14 mutations in non-small-cell lung cancer are associated with advanced age and stage-dependent MET genomic amplification and c-Met overexpression](https://onco.cc/key-papers/paper-awad-met-exon-14-mutations-lung-jco-2016/), [MET exon 14 splicing alterations across tumour types and their sensitivity to MET inhibitors](https://onco.cc/key-papers/paper-frampton-met-exon-14-cancer-discov-2015/), [Molecular characterization of KRAS wild-type tumors in patients with pancreatic adenocarcinoma](https://onco.cc/key-papers/paper-philip-kras-wild-type-pancreatic-ccr-2022/), [Molecular mechanisms of resistance to first- and second-generation ALK inhibitors in ALK-rearranged lung cancer](https://onco.cc/key-papers/paper-gainor-alk-resistance-mutations-cancer-discov-2016/), [NILE: clinical utility of comprehensive cell-free DNA analysis to identify genomic biomarkers in patients with newly diagnosed metastatic non-small cell lung cancer](https://onco.cc/key-papers/paper-leighl-nile-cfdna-tissue-genotyping-ccr-2019/), [Prospective comprehensive molecular characterization of lung adenocarcinomas for efficient patient matching to approved and emerging therapies](https://onco.cc/key-papers/paper-jordan-prospective-lung-adenocarcinoma-msk-cancer-discov-2017/), [Reciprocal feedback regulation of PI3K and androgen receptor signalling in PTEN-deficient prostate cancer](https://onco.cc/key-papers/paper-carver-pi3k-ar-reciprocal-feedback-prostate-cancer-cell-2011/), [Recurrent R-spondin fusions in colon cancer](https://onco.cc/key-papers/paper-seshagiri-rspo-fusions-colon-nature-2012/), [Resensitization to crizotinib by the lorlatinib ALK resistance mutation L1198F](https://onco.cc/key-papers/paper-shaw-alk-l1198f-resensitisation-nejm-2016/), [ROS1 rearrangements define a unique molecular class of lung cancers](https://onco.cc/key-papers/paper-bergethon-ros1-rearrangements-lung-jco-2012/), [Trastuzumab deruxtecan in patients with HER2-positive advanced colorectal cancer (DESTINY-CRC02): primary results from a multicentre, randomised, phase 2 trial](https://onco.cc/key-papers/paper-destiny-crc02-lancet-oncol-2024/), [Tucatinib plus trastuzumab for chemotherapy-refractory, HER2-positive, RAS wild-type unresectable or metastatic colorectal cancer (MOUNTAINEER)](https://onco.cc/key-papers/paper-strickler-mountaineer-tucatinib-trastuzumab-lancet-oncol-2023/), [Updated molecular testing guideline for the selection of lung cancer patients for treatment with targeted tyrosine kinase inhibitors](https://onco.cc/key-papers/paper-lindeman-lung-molecular-testing-guideline-jto-2018/), [Using multiplexed assays of oncogenic drivers in lung cancers to select targeted drugs](https://onco.cc/key-papers/paper-kris-lung-cancer-mutation-consortium-jama-2014/), [Whole-exome and targeted gene sequencing of gallbladder carcinoma identifies recurrent mutations in the ErbB pathway](https://onco.cc/key-papers/paper-li-gallbladder-exome-erbb-nat-genet-2014/), [Yarden and Sliwkowski 2001: untangling the ErbB signalling network](https://onco.cc/key-papers/paper-yarden-sliwkowski-erbb-network-nrmcb-2001/)
- biomarkers: [ALK kinase-domain resistance mutation (G1202R and the rest)](https://onco.cc/biomarkers/alk-resistance-mutation/), [EGFR C797S (and its phase with T790M)](https://onco.cc/biomarkers/egfr-c797s/), [NRG1 gene fusion](https://onco.cc/biomarkers/nrg1-fusion/)

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