Tyrosine kinases phosphorylate downstream substrates → MAPK / PI3K-AKT / JAK-STAT cascades that drive proliferation. Oncogenic fusion (BCR-ABL in CML, philadelphia-chromosome+ ALL), receptor amplification (HER2 in breast), or activating mutation (EGFR in NSCLC, c-KIT in GIST) makes tumors kinase-addicted. Small-molecule TKIs (imatinib first, 2001) bind the ATP cleft of the kinase. Imatinib targets BCR-ABL + c-KIT + PDGFR; nilotinib + dasatinib are 2nd-/3rd-gen BCR-ABL TKIs covering imatinib-resistant mutations (T315I escapes both — needs ponatinib). EGFR-TKIs (erlotinib, gefitinib, osimertinib, afatinib) for NSCLC. Multi-target TKIs (sorafenib, sunitinib, pazopanib, lenvatinib) hit VEGFR + PDGFR + RAF + others — broader-spectrum antiangiogenesis + antiproliferation. JAK-i (ruxolitinib, tofacitinib) covered in jak_stat_signaling.
Organ Systems
immune-hematologic
integumentary
Pathway Steps
tyrosine-kinase-active → downstream-phosphorylation — via ATP binding + substrate phosphorylation → MAPK / PI3K / JAK-STAT activation. Receptor and non-receptor tyrosine kinases phosphorylate downstream substrates to drive proliferation and survival; their constitutive activation (by mutation or fusion, e.g. BCR-ABL) drives many cancers. Tyrosine kinase inhibitors (imatinib, the “-tinibs”) block the ATP-binding site — imatinib’s success in CML launched the era of targeted cancer therapy.
Known Modulators
imatinib (inhibitor) — BCR-ABL + c-KIT + PDGFR. first TKI (2001); CML transformed from leukemia to chronic disease; CYP3A4 substrate (verapamil/macrolide DDIs)