Targeting G2M

• Advantages of genomic instability to cancer cells

  • Activation of oncogenes or loss of tumour suppressors
  • Gene fusions: BCR-Abl
  • Increase genetic diversity, which increases heterogeneity and leads to polyclonal tumours
  • Promotes resistance to therapy
  • Loss of genes that are recognised by the immune system promotes immune evasion.
  • Overexpression of factors such as VEGF, promotes modulation of the TME
• Describe the mitotic checkpoint

  • CDC20 activates the APC complex when all the chromosomes are attached to the centrosomes
  • This leads to degradation of cyclin B and securin (holds separase), which allows the cell cycle to progress
  • Once Cdk1 is inactive and stops signalling, separase can release the chromatids, allowing them to separate.
• Describe the damage threshold

  • Division will occur first if cyclin B levels fall fast enough to reach the threshold to cause division
  • Cell death will happen first if damage signals accumulate faster than cyclin B levels fall
  • Targeting mitosis aims to stall cells long enough for the damage threshold to be reach first
• Describe microtubule inhibitors

  • Vinca alkaloids: inhibits formation of microtubules
  • Taxanes: inhibit depolymerisation
  • Both are cell cycle specific as they act in M phase
  • Leads to G2/M arrest
  • Cancer cells are replicating rapidly their microtubules are always working and therefore are targeted by these drugs.
  • This means that other rapidly dividing cells in tissues such as hair follicles, the GI tract and blood production will be targeted.