Neurosurgery notes/Tumours/Tumour general/Treatment for brain tumours/Mechanism of treatment resistance

Mechanism of treatment resistance

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Treatment for brain tumours
  • Uncertain drug delivery
    • Partial BBB preservation
    • High interstitial pressure in tumour tissue
  • Invasiveness of Glioblastoma that allow them to spread far within the CNS and remain behind intact BBB
  • Retention of DNA repair machinery that reduces effectiveness of chemo and radiotherapy
  • Intratumoural heterogeneity and genomic instability resulting in colonal population of resistant cells
  • Presence of population of tumour -initiating or stem cell-like cells that may harbour resistance mechanisms distinct from those of the majority of bulk of tumour
  • Secondary oncogenic can changes induced by tumour progression
Malignant glioma and therapeutic resistance. Glioblastomas are adept at evading inhibition of EGFR receptor function through several possible mechanisms. (1) Brain tumour cells that are intractable to DNA damage-induced apoptosis may also tolerate apoptotic cues driven by TKI-mediated inhibition of EGFR. Combinatorial therapy using inhibitors of anti-apoptotic activity may overcome this cross-resistance. (2) Intratumoural diversity within glioblastomas may drive resistance to single agent-based anti-EGFR therapy due to: RTK co-activation, PTEN deletion/mutations, and tumour cell-tumour cell interactions via secreted molecules. PTEN denotes mutation. (3) Efflux of EGFR TKIs and increased genetic stability may lead to the maintenance of cancer stem cell populations and tumour relapse. (4) Enhanced immunosuppression mediated by circulating growth factors, cytokines, and suppressor T cells can antagonize the systemic immune responses generated by anti-EGFR immunotherapies. Additionally, circulating IL6 in the tumour microenvironment can facilitate resistance intracellularly via activation of the JAK/STAT3/Bcl-xL pathway. Reprinted from Taylor TE et al. (2526A).
Malignant glioma and therapeutic resistance. Glioblastomas are adept at evading inhibition of EGFR receptor function through several possible mechanisms.
(1) Brain tumour cells that are intractable to DNA damage-induced apoptosis may also tolerate apoptotic cues driven by TKI-mediated inhibition of EGFR. Combinatorial therapy using inhibitors of anti-apoptotic activity may overcome this cross-resistance.
(2) Intratumoural diversity within glioblastomas may drive resistance to single agent-based anti-EGFR therapy due to: RTK co-activation, PTEN deletion/mutations, and tumour cell-tumour cell interactions via secreted molecules. PTEN denotes mutation.
(3) Efflux of EGFR TKIs and increased genetic stability may lead to the maintenance of cancer stem cell populations and tumour relapse.
(4) Enhanced immunosuppression mediated by circulating growth factors, cytokines, and suppressor T cells can antagonize the systemic immune responses generated by anti-EGFR immunotherapies. Additionally, circulating IL6 in the tumour microenvironment can facilitate resistance intracellularly via activation of the JAK/STAT3/Bcl-xL pathway.
Reprinted from Taylor TE et al. (2526A).