Cancer - Drug Resistance

What is drug resistance?

When a cell does not repond to a drug from the outset or fails to respond to a dose of drug which was effective previously

How can cells survive in the presence of a toxin?

Inactivation of the drug

Alterations of the drug sensitive site

Decreased drug accumulation

Development of alternative pathway

What is tolerance?

Cells/organisms become less sensitive to a compound over time

A greater amount of drug is needed to elicit the same effect (bad in cancer bc therapy already toxic)

What is intrinsic (de novo) resistance?

Present before treatment is administered

Results in the inherent ability of cancer cells to survive at clinically relevant concentrations of a drug

Poor initial response to treatment given indicates intrinsic resistance

What is aquired resistance?

Occurs after an intial positive reponse to the therapy

Cancer cells gradually aquire specific genetic abnormalities or protien alterations that result in unresponsiveness to treatment and cancer relapse

Requires previous exposure to drug

What is multi-drug resistance (MDR)?

Cells aquire resistance to a single cytotoxic agent yet display a broad unpredictable cross resistance to a wide variety of unrelated cytotoxic drugs

What are the various mechanisms of resistance?

Decreased drug influx

Increased drug efflux

Mutations of drug target

DNA damage repair altered

Activation of alternative signalling pathways

Evasion of apoptosis

What are the different models which portray resistance and genomic instability/cell plasticity?

Therapy induced mutation model

• No fully resistant subclone is present at diagnosis and rather therapy induced mutations drive relapse

Therapy selection model

• A minority of drug-tolerant subclone survives therapy and aquires additional mutations that lead to cancer relapse

De novo resistance model

• Most cells are intially therpay resistant and remission is never achieved

How can ATP-Binding Cassettes (ABC transporters) cause resistance?

ABCs are active drug efflux pumps which have 3 main modes of efflux

1. Classical - pumps drug straight out of cell

2. Hydrophobic - pumps drug out of membrane (drug enters membrane)

3. Flippase/Pore - pumps drug from inner leaflet of membrane to outer leaflet

What drugs can counteract ABC resistance?

Verapamil, Cyclosporin A, Zosuquidar

Given in combination with anticancer drugs to help prevent/reverse multi-drug resistance

How can cancer cells evade apoptosis?

Abberant pathways may result in failure of apoptic machinery
Cancer cells may alter how p53 response to DNA damage which may limit the efficacy of chemo

How can alterations in DNA repair lead to drug resistance?

Normally Poly-ADP Ribose Polymerase (PARPs) repair damaged DNA which allows cell survival

By inhibiting PARP the cancer cell accumulates multiple single strand breaks which without repair become double strand breaks which triggers cell death via apoptosis (only in BRCA1/2 deficient tumours as BRCA1/2 repairs the ds break)

Cancer cells have aquired resistance to PARP inhibitors

How may cell surface receptor malfunction lead to drug resistance?

Protein mutation causing constitutively activation of the extracellular domain causing growth in the absence of GF

Genetic changes causing overexpression of normal or constitutively active receptors

Tumour cell production of GF leads to an autocrine loop and a constitutively active receptor

How may the tumour microenvironment cause drug resistance?

Physical or chemical features of the TME including hypoxia, acidity, oxidative stress and inflammation may facilitate tumour progression and resistance