• Growth factor binds to extracellular domain of receptor
• Ligand binding causes the receptors to form dimers (either a homodimer or heterodimer)
• The conformational change is transmitted through the transmembrane region to the intracellular domain
• The tyrosine kinase is activated and undergoes autophosphorylation of the intracellular tyrosine domains
• The kinase domain of the receptor phosphorylates other tyrosines on intracellular proteins which intitiates intracellular signaling pathways leading to cell division and survival

• Growth factor binds to extracellular domain of receptor
• Ligand binding causes the receptors to form dimers (either a homodimer or heterodimer)
• The associated kinase is not part of the intracellular domain of the receptor
• The associated tyrosine kinase binds the intracellular domain of the receptor through non-covalent interactions
• Receptor dimerization causes activation of associated tyrosine kinase
• The associated tyrosine kinase phosphorylates intracellular target proteins

• When tumors reach their maximal size the cells experience low O2 tension --> this triggers a transcriptional response
• As a result of the transcriptional response, the tumor produces pro-angiogenic factors such as VEGF
• Tumor production of VEGF (and other factors) causes sprouting of new blood vessels from pre-existing vessels nearby
• The process of vessel formation is characterized by certain endothelial cell activities (proliferation, migration, and organization into tubules)

• Low O2 tension results in increased [HIF-1alpha]
• HIF-1alpha translocates into the nucleus and dimerizes with HIF-1beta
• The HIF-1alpha/beta complex transcribes genes that encode for factors that induce angiogenesis (VEGF, PDGF, TGF)

• Tumor produces VEGF that stimulates nearby cells of pre-existing blood vessels
• Binding of VEGF to its receptor on endothelial cells activates gene transcription in endothelial cells
• The endothelial cells produce other factors (autocrine and paracrine) that are part of the angiogenesis process --> they stimulate progression through the cell cycle, cell migration and organization of endothelial cells into tubules that will mature into fuctional blood vessels

• Increased vascular permeability
• Greater endothelial cell survival
• Progression through the cell cycle
• Migration of endothelial cells and organization of endothelial cells into tubules

Inhibitor of Receptor Tyrosine Kinase

• Blocks ATP binding
• Acts on the intracellular domain to inhibit tyrosine kinase activity of epidermal growth factor receptor (EGFR)
• Cell cycle arrest and apoptosis

Inhibitor of Receptor Tyrosine Kinase

• Blocks ATP binding
• Acts on the intracellular domain to inhibit tyrosine kinase activity of epidermal growth factor receptor (EGFR)
• Cell cycle arrest and apoptosis

Inhibitor of Receptor Tyrosine Kinase

• Blocks ATP binding
• Acts on the intracellular domain to inhibit tyrosine kinase activity of epidermal growth factor receptor (EGFR)
• Cell cycle arrest and apoptosis

Inhibitor of Receptor Tyrosine Kinase

• Inhibits phosphorylation of kinase receptors -- most likely the auto-phosphorylation step
• Inhibits many different receptor tyrosine kinases (PDGF, VEGF, KIT, CSF, and others)

Inhibitor of Non-Receptor Tyrosine Kinase

• Inhibits ABL kinase
• Efficacy against CML attributed to BCR-ABL gene fusion (Philadelphia chromosome) product
• Also inhibits Src kinase (a kinase that phosphorylates RAS -- the beginning of the MAP kinase pathway)

AKA Philadelphia Chromosome

• Nearly all CML patients have the t(9,22) translocation
• The reciprocal exchange of DNA sequence results in a long chromosome 9 and a short chromosome 22 with fusion of ABL and BCR genes
• The fused genes result in protein fusion of ABL and BCR
• The ABL-BCR protein has increased ABL kinase activity resulting in hyper-proliferation of granulocytes (CML)

• Hematopoietic stem cells acquire the Philadelphia Chromosome
• The translocation resulting in the BCR-ABL fusion causes the kinase activity of ABL to be constitutively active (does not require presence of growth factor for activation)
• The constitutive activity of ABL causes selective proliferation of granulocytes

• Rash
• Acne
• Diarrhea
• Potential for drug-drug interactions through CYP3A4 and 3A5
• Sunitinib can also cause HTN, asthenia, and wound healing concerns

• Myelosuppression
• Prolonged QT interval
• CYP3A4 metabolism

Mixed Kinase Inhibitor

• Inhibits BCR-ABL, PDGF, and KIT

Resistance

• Kinase domain mutations
• Gene amplification

ADRs

• Dermatological
• GI
• Edema

Mixed Kinase Inhibitor

• Inhibits RAF, KIT, VEGF, PDGF
• Results in cell cycle inhibition, decreases cell survival, and interferes with angiogenesis

ADRs

• Hand-foot reaction common
• Wound healing concern

Inhibits mTOR

• Inhibits cell division

ADRs

• Hyperglycemia
• Wound healing difficulty (decreased HIF)

Inhibits mTOR

• Inhibits cell division

ADRs

• Hyperglycemia
• Wound healing difficulty (decreased HIF)

• Antibody dependent cell mediated toxicity
• Complement-dependent cytotoxicity
• Receptor activation and induction of apoptosis
• Block growth factor activity
• Antibodies can be conjugated (derivatized) to a cytotoxic chemical or a radioactive isotope

MOA

• Inhibits ligand binding to EGFR
• Apoptosis, interferes with cell proliferation

ADRs

• Infusion reactions --> sometimes serious
• Acne, rash common

MOA

• Inhibits ligand binding to EGFR
• Apoptosis, interferes with cell proliferation

ADRs

• Infusion reactions --> sometimes serious
• Acne, rash common

MOA

• Binds VEGF and blocks activation of VEGF receptor
• Inhibits angiogenesis

ADRs

• GI perforation
• Abnormal/slow wound healing
• Hemorrhage

MOA

• Blocks binding of growth factors to HER2 epidermal growth factor receptor --> inhibits proliferation and induces apoptosis
• The antibody binds the receptor on tumor cells and a killer T cell binds the Fc domain of the antibody

ADRs

• Congestive heart failure
• Left ventricular dysfunction

MOA

• Bind CD20 antigen which is expressed through pre-B cell stage to mature plasma cells
• Induces immune attack (antibody-dependent cell mediated toxicity)
• Results in apoptosis

ADRs

• infusion rxns
• Tumor lysis syndrome
• Renal Tubule uric acid crystals
• Cytopenias

MOA

• Bind CD20 antigen which is expressed through pre-B cell stage to mature plasma cells
• Induces immune attack (antibody-dependent cell mediated toxicity)
• Results in apoptosis

ADRs

• Infusion rxns
• Renal Tubule uric acid crystals
• Cytopenias

MOA

• Bind CD20 antigen which is expressed through pre-B cell stage to mature plasma cells
• Induces immune attack (antibody-dependent cell mediated toxicity)
• Results in apoptosis
• ¹³¹I emits beta and gamma radiation --> CD20 is not inernalizaed which means antibody will not be taken up by the cell

ADRs

• Infusion rxns
• Renal Tubule uric acid crystals
• Cytopenias
• Hypothyroidism

MOA

• CD33 is expressed on AML cells
• Antibody binds to the CD33 and is internalized
• Gemtuzumab is a derivative of calicheamicin which is a potent anti-tumor antibiotics that binds the minor groove of DNA --> results in strand breakage and cell death

ADRs

• Infusion reactions
• Myelosuppression
• Hepatotoxicity and Veno-occlusive disease

MOA

• Antibody-dependent cell-mediated
• Complement activation

ADRs

• Infusion reactions
• Neutropenia
• Risk of infection

Inhibitor of Non-Receptor Tyrosine Kinase

• Inhibits ABL kinase
• Efficacy against CML attributed to BCR-ABL gene fusion (Philadelphia chromosome) product
• Also inhibits Src kinase (a kinase that phosphorylates RAS -- the beginning of the MAP kinase pathway)