9. Oncology Drugs: Kinase Inhibitors

Key challenges in anticancer therapy

Current strategies to improve specificity for anticancer therapies

MOA of kinases

Kinase based signaling pathways as anticancer drug targets part 1

• Growth factor receptors:

  • ex: EGFR, HER2, ALK

  • these receptors sit in the cell membranes and when a growth signal (ligand) binds, the two receptors pair together forming a dimerization, their internal kinase domains activate, and they send signals into the cell

• Kinase signaling cascades spread the message

  • ex: RAS, RAF, MEK, PI3K, AKT, BCR-ABL

  • A kinase is basically an enzyme that turns other proteins on by adding phosphate groups - Phosphorylation

• Cancer occurs when the pathway gets stuck “on” leading to over activation, permanently/constitutively active

Kinase based signaling pathway as anticancer drug targets part 2

• Tumor suppressors normally act as brakes to such signaling down

  • ex: PTEN phosphatase - inhibitory “break pedal” intracellular protein

• Tumors build their own blood supply - angiogenesis

  • cancer cells release VEGF that binds to VEGFR on endothelial cells stimulating angiogenesis

• Tumors “hide” from the immune system

  • Cancer cells express PD-L1

  • T cells express PD-1

  • when PD-L1 binds to PD-1, the T cell gets turned off causing immunosuppression - shuts off the T cells that kill cancer cells by using checkpoint proteins ex: PD-L1

Epidermal growth factor receptor (EGFR), a receptor tyrosine kinase, aka HER1 Inhibitors

• Agents - distinguish between gen 1, 2, 3

• Indication

• Tox

• Testing

• non-small cell lung cancer (NSCLC) most common type of lung cancer

Human epidermal growth factor receptor (HER2), a receptor tyrosine kinase Inhibitors

• Agents

• Indication

• Warning

• Testing

Anaplastic lymphoma kinase (ALK), a receptor tyrosine kinase Inhibitor

• Agents

• Indication

• Warnings

• ADR

• Testing

Inhibitors of B-Raf proto-oncogene, serine/threonine kinase (BRAF)

• Agent

• Indication

• Warning (3)

• ADR

• Testing

Inhibitors of MEK (MAPK/ERK kinase, serine/threonine kinases)

• Agent

• MOA

• Indication

  • what is it used in combo with

• Side effects (2)

• Pharm testing

Inhibitors of BCR-ABL (an abnormal fusion tyrosine kinase from gene translocation)

• Agent

• MOA

• Indication

• Testing

Inhibitors of mTOR (mammalian target of rapamycin a serine/threonine kinase)

• prototype inhibitor

• indication

• what does mTOR do

• what does inhibiting mTOR do (4)

• C/I’s (2)

Inhibitors of Multiple Tyrosine Kinases

• Agents (2)

• MOA of each agent

• Indication

• Tox (4)