Protein Kinase Inhibitors in Cancer Chemotherapy

Protein Kinase Inhibitors in Cancer Chemotherapy

1. Definition, scope & rationale for pathway-targeted therapy

• Pathway-targeted (molecularly targeted) anticancer drugs are agents designed to block specific oncogenic molecular changes that drive malignant progression, in contrast to classic cytotoxic chemotherapy that targets DNA/mitosis non-selectively (G&G 14e Ch.71, p.1383).
• Development relies on the discovery of driver mutations — molecular changes that a cancer becomes "addicted to" (oncogene addiction) for continued proliferation and survival; this dependence creates a therapeutic window wider than that of cytotoxics, with a different adverse-effect spectrum (Golan 4e Ch.40, pp.757–758, p.764).
• The three biological drivers of cancer growth that targeted drugs attack (Hanahan & Weinberg "Hallmarks of Cancer") are: oncogenic pathways in malignant cells (mutant receptors/kinases), the tumour-microenvironment reaction (angiogenesis), and escape from host immune surveillance (G&G 14e Ch.71, p.1383).
• Two pharmacologically distinct classes of pathway-targeted drugs (G&G 14e Ch.71, p.1384; KDT 8e Ch.64, p.928):
  • Small molecules (molecular mass <1 kDa) — enter cells and engage intracellular targets (mostly the kinase ATP-binding pocket); oral; often inhibit multiple kinases (broader spectrum of desired + off-target + adverse effects); hepatic-CYP metabolised; elimination t½ typically 12–24 h ⇒ usually once-daily oral dosing. This chapter's subject.
  • Monoclonal antibodies (IgG ~150 kDa) — recognise cell-surface/shed antigens (extracellular); parenteral; highly specific for a single antigen; eliminated over days–weeks (covered in G&G Ch.72; KDT lists cetuximab, trastuzumab, bevacizumab, rituximab here).
• The seven mechanistic categories of small-molecule pathway-targeted drugs (G&G 14e Ch.71, p.1383):
  • I. Altered growth-factor receptor signalling (receptor tyrosine kinases + Hedgehog)
  • II. Activation of intracellular protein kinases (RAS–RAF–MEK–ERK, JAK, CDK4/6, BTK, BCR-ABL, PI3K/AKT/mTOR, multikinase)
  • III. Cancer-cell–host interactions and aberrant angiogenesis
  • IV. Defects in DNA repair (PARP inhibitors)
  • V. Altered protein degradation (IMiDs/cereblon modulators, proteasome inhibitors)
  • VI. Altered epigenetic regulation (HDAC, HMT, IDH1/2)
  • VII. Other targets controlling cancer-cell behaviour (BCL2, nuclear export, translation, CXCR4)

Note on scope: the term protein kinase inhibitors (PKIs) is the chapter's headline, but the G&G chapter (and this topic) deliberately covers the full sweep of pathway-targeted small molecules — including non-kinase targets (PARP, proteasome, cereblon, BCL2, HDAC) — because they share the "block a specific oncogenic node" logic. Sections 14–18 below are the non-kinase appendices to the kinase-inhibitor core.