🧪 MAPK/ERK Pathway — Oncology Target Map

Built with KiuClavis · Provenance-First Biomedical Intelligence
🧬 v6 (finalized) — added SOS (GEF, activates RAS) and NF1 (GAP, inhibits RAS) as the accelerator/brake pair around RAS, plus narrative framing on select nodes (look for 📖 chapter callouts) · built on the mechanism layer (PTEN, DUSP6/SPRY, 4 resistance routes), gedatolisib's multi-target bracket, CDK4/6 convergence, and the PI3K/AKT/mTOR branch · tap anything for detail
Growth Factor Receptors (TKI Targets) → RAS/PI3K branch point → CDK4/6–Cyclin D → Cell Cycle RECEPTOR TYROSINE KINASES — TKI TARGETS TRANSCRIPTION FACTORS — PATHWAY OUTPUT PI3K/AKT/mTOR — PARALLEL SURVIVAL PATHWAY via p85/p110 (also drives protein synthesis & metabolism, not shown) MYC + AP-1 induce Cyclin D1 transcription RAS-GTP directly binds PI3K (p110) ⚠ RTK bypass ⚠ feedback loss ERK induces ↑ ⚠ cross-pathway bypass reverses PIP3 → PIP2 ⚠ RB1 loss / CDK6 amp EGFR / HER2 (ERBB Family) ALK / ROS1 Fusion Kinases MET (c-MET) RET Proto-oncogene KIT / PDGFRA GIST · SM FGFR1–4 Receptors NTRK1–3 (TRK A/B/C) BCR-ABL1 (Ph Chromosome) RAS KRAS · NRAS · HRAS RAS RAF BRAF · CRAF · ARAF RAF MEK1/2 (MAP2K1/2) MEK1/2 ERK1/2 (MAPK3/1) no approved direct inhibitor yet ERK1/2 ELK1 / SRF Immediate-Early Genes no approved direct inhibitor yet MYC Master Regulator no approved direct inhibitor yet FOS / JUN (AP-1 Complex) no approved direct inhibitor yet ETS Family (ERG, ETV1/4/5) no approved direct inhibitor yet PI3K PIK3CA · PIK3R1 AKT (PKB) AKT1/2/3 mTOR mTORC1 / mTORC2 💊 gedatolisib (Revtorpyk) pan-PI3K + mTORC1/2 — one drug, two nodes PTEN tumor suppressor DUSP6 / SPRY negative feedback NF1 GAP — turns RAS off accelerates GTP → GDP GRB2–SOS (GEF) CONVERGENCE POINT CDK4/6 – Cyclin D RB / E2F Checkpoint 🧬 RB Phosphorylation → E2F Release → S-Phase Entry (Cell Division)
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COLOR LEGEND
Receptor tyrosine kinases (RTKs) — TKI targets, feed both branches below
RAS (KRAS/NRAS/HRAS) — the molecular on/off switch
RAF (BRAF/CRAF/ARAF)
MEK1/2
ERK1/2 — terminal MAPK kinase
Transcription factors — MAPK pathway output
PI3K · AKT · mTOR — parallel survival/growth branch
CDK4/6 · Cyclin D — where both branches converge on the cell cycle
Dashed outline = no FDA-approved product directly targets this node yet
PTEN · DUSP6/SPRY · NF1 · SOS — regulator mechanisms, no direct approved drug (T-bar = inhibits, arrow = activates)
Solid white bracket = one multi-target drug spanning several nodes at once — tap it for the drug's own profile
Dashed rose arrow/T-bar = a resistance route — tap it for mechanism & countermeasures
Dotted gray line = direct crosstalk between the two branches (not resistance)
💡 Tap any box, bracket, or rose arrow for mechanism, genes, associations, and (where relevant) countermeasures.
📖 A few nodes (CDK4/6, MYC) open with a short narrative frame before the clinical detail — more chapters to come.
⚠️ Drug lists are representative, not exhaustive, and reflect FDA approvals as of early Sept 2026 — always confirm current label/indication before clinical use.

This is a deliberately curated v2, not an exhaustive map: the RTK row shows eight representative TKI-relevant targets rather than every receptor that can feed these two pathways (VEGFR and IGF1R, for example, also signal in), both cascades are drawn as simplified linear chains for clarity despite heavy real-world crosstalk and scaffold-protein complexity, and the three resistance arrows illustrate well-documented escape mechanisms rather than an exhaustive resistance atlas. Genetics and treatment summaries are illustrative starting points, not exhaustive drug labels or a substitute for current prescribing information.

⚠️ Biochemical Basis for Combined RAF and MEK Inhibition. Monotherapy with type I BRAF inhibitors in BRAF-mutant cancers can induce paradoxical transactivation of wild-type RAF dimers in the presence of upstream RAS-GTP. Furthermore, selective inhibition of either RAF or MEK relieves negative feedback dephosphorylation mediated by DUSP6 and SPRY, restoring ERK phosphorylation and driving rapid acquired resistance. Consequently, clinical standards of care employ combination doublets: dabrafenib plus trametinib, vemurafenib plus cobimetinib, or encorafenib plus binimetinib, which achieve sustained pathway suppression and delay emergent resistance.
⚠️ Mechanisms of Acquired Resistance: Pathway Bypass and Feedback Reactivation. Complete pharmacological blockade of a single oncogenic kinase frequently triggers adaptive resistance through alternative signaling routes. Malignant cells may upregulate alternative receptor tyrosine kinases (RTK bypass via MET or EGFR amplification), reactivate intrinsic signaling via loss of negative regulators like DUSP6 (feedback reactivation), or shift oncogenic dependence to the parallel PI3K/AKT/mTOR survival pathway (cross-pathway bypass). Rational therapeutic regimens address these escape trajectories through structured dual-pathway combinations and pan-isoform inhibitors.