# IGF1R **Receptor Tyrosine Kinase** IGF1R is a ligand-activated receptor tyrosine kinase that couples extracellular growth cues to intracellular anabolic and survival programs. In small round blue cell sarcomas, including DSRCT and Ewing-related tumours, the IGF axis frequently converges on **PI3K–AKT** and **RAS–MAPK**, shaping proliferation, metabolism, and therapy response. ## Overview The IGF1R receptor forms homodimers (or hybrid receptors with INSR) and, upon ligand binding (IGF‑1/IGF‑2), autophosphorylates tyrosines on its intracellular β-subunits. Docking proteins such as **IRS1/2** recruit **PI3K** and adaptor complexes that engage **SOS–RAS**, driving downstream **AKT/mTOR** and **MEK/ERK** signalling. Negative regulation arises via **PTEN**, phosphatases, and receptor internalisation.  ## Key Mechanisms - **Ligand binding → autophosphorylation → IRS1/2 recruitment** - **PI3K activation (PIP2→PIP3)** leading to **AKT** phosphorylation (PDK1/mTORC2) - **RAS/MAPK activation** via adaptor complexes (e.g., GRB2/SOS, SHP2) - **Feedback**: mTORC1/ERK feedback loops, receptor downregulation, SOCS proteins - **Cross‑talk** with **insulin receptor (INSR)** and metabolic control ## Clinical Relevance - **Targetability**: monoclonal antibodies (ligand blocking or anti‑receptor) and small molecules have been explored; context and hybrid receptors influence response. - **Biomarkers**: IRS1 levels, pathway phosphorylation states, ligand abundance (IGF‑2), and **PTEN** status may modulate sensitivity. - **Resistance routes**: pathway bypass via alternate RTKs (e.g., **MET**, **AXL**), INSR compensation, or downstream mutations. ## Research Findings **Key Studies (placeholders—replace with curated refs):** - **IGF axis activation in Ewing/DSRCT**: dependence on IGF signalling for proliferation and survival. [add pmid] - **IRS1 coupling**: essential adaptor for PI3K recruitment. [add pmid] - **Combination strategies**: IGF1R + **mTOR** or **DDR** inhibitors show synergy in some models. [add pmid] **Therapeutic Implications** - **Direct blockade**: anti‑IGF1R mAbs; ligand traps. - **Pathway**: **PI3K/mTOR** inhibitors; **MEK** inhibitors for MAPK branch. - **Combos**: IO + metabolic/PI3K axis; IGF + DDR concepts to limit adaptive repair. **Outstanding Questions** - What biomarkers best predict durable response to IGF1R blockade in DSRCT/Ewing? - How do hybrid receptors (IGF1R/INSR) influence drug sensitivity? - Which microenvironmental cues (e.g., IGF‑2 sources) sustain signalling after therapy? ## DSRCT‑Specific Context DSRCT often exhibits signalling dependencies that converge on IGF1R/PI3K. Curate whether EWS‑WT1 programs upregulate ligands/receptors/adaptors, and map cross‑talk with **mTOR**, **EZH2/epigenetic** control, and **DDR** pathways in resistant states. ## Experimental Models - **JN‑DSRCT‑1** and related lines: document baseline IGF pathway activity and drug responses. - **Xenografts/PDX**: summarise sensitivity to IGF1R/PI3K/mTOR agents. - **Perturbations**: IRS1 knockdown, PTEN re‑expression, ligand neutralisation. ## Future Directions - Stratified trials using **biomarker‑guided** combinations (IGF1R + PI3K/mTOR; IGF1R + DDR). - Map **adaptive rewiring** with time‑course phospho‑proteomics/RNA‑seq. - Evaluate **metabolic phenotypes** under IGF blockade (glucose uptake, lactate export). --- ## Sources Replace the placeholders above with curated citations (PMIDs/DOIs). Keep a short, high‑quality list. ## Related Topics - [PI3K–AKT Pathway](/signaling/pi3k-akt) - [RAS–MAPK Pathway](/signaling/ras-mapk) - [mTOR Signalling](/signaling/mtor) - [DDR Pathways](/resistance/ddr-pathways) - [Receptor Tyrosine Kinases](/signaling/rtks) --- ## Tags `#scale/molecular` `#receptor/rtk` `#axis/igf` `#dsrct/signaling` `#tx/target` `#conf/tbd` ## Last Updated September 2025 — scaffold created; add evidence, models, and figures.