Lecture notes from Imperial College London, Medical Biosciences BSc, 2nd year, Cancer Biology (CBIO) module
learning outcomes:
- Define cancer therapeutic resistance
- Explain some of the different mechanisms of drug resistance
- Describe how cancer stem cells and epigenetic changes can giv...
Resistance, biomarkers, perso treatment
Introduction
- secondary mutation restores the function of BRCA1/BRCA2, resulting in resistance to PARPi:
Therapy resistance in cancer
- resistance can occur via genetic & epigenetic changes in cancer cells/ tumour microenvironment
(ex: increased matrix stiffness in liver cancers) 1) changes within cancer cells
give rise to
2) CSCs
resistance
- overcome resistance 3) epigenetic changes
=> alternative drug working via ≠ mechanisms
=> design drugs that specifically target this resistance
=> combination of therapies to target ≠ aspects of the tumour
=> personalised treatment
Drug resistance in cancer
- diagnosis (1st) = identifying the problem and giving it a name
- prognosis (2nd) = prediction of the course of the disease, treatments and results
=> poor for patients w/ metastatic cancer: 90% of chemo failure are related to drug resistance
- pharamacodynamics (PD) = how a drug affects the organism
- pharmacokinetics (PK) = how the organism affects the drug
, - drug absorbed - distributed => taken inside the cancer cell (drug influx) + activated to kill cells
=> drug efflux & metabolised - eliminated for patient safety
limit amount of drug reaching tumour
- drug activity also limited by
=> poor influx/ excessive efflux
=> drug inactivation/ lack of activation
=> alterations in drug target
=> activation of adaptive prosurvival responses
=> lack of cell death due to dysfunctional apoptosis
Mechanisms of drug resistance
- decreased uptake (influx)
=> methotrexate (toxic folic analogue): mutation of one/ both folate transporters to enter cells
=> nucleoside analogues: mutation of specific nucleoside transporters
=> cisplatin (chemotherapy): reduction in plasma membrane receptors, transporters & endocytosis
- increased drug efflux
=> P-glycoprotein (Pgp): ATP binding protein pump => pumps foreign substances out of cells
=> overexpression associated w/ resistance (doxorubicin, taxanes, vinca alkaloids)
=> inhibition of Pgp with verapamil can reverse drug resistance
- altered drug metabolism to increase detoxification
=> glutathione (GSH): antioxidant that protects the cells
=> conjugates to platinum chemo drugs & modif them to substrates for ABC transporters
(efflux)
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