33 Drug Resistance

Question 1

2 classes of resistance

DEFINE both

Answer 1

Intrinsic - present BEFORE the Tx

Acquired - develops DURING the Tx

Question 2

3 reasons why ACQUIRED resistance occurs?

Answer 2

1. Subpopulations survive and REGEN the tumor
2. New mutations arising during Tx
3. ADAPTIVE response to compensate

Question 3

2 major FACTORS affecting resistance

DEFINE these

Answer 3

Pharmacokinetics - what BODY does to the drug

Pharmacodynamics - what CELL does to the drug

Question 4

Explain pharmacokinetics

Answer 4

What the BODY does to the drug

= LIMITS amount of drug reaching the tumor

Question 5

List some ASPECTS of pharmacokinetics

Answer 5

Metabolism
Absorption
Distribution
Degradation

Question 6

List some ASPECTS of pharmacodynamics

Answer 6

What CELLS do to drugs

• Influx
• Cellular - activation, target, response
• Efflux

Question 7

What are some issues that can arise during DELIVERY

Answer 7

COMPLEX tissues must be crossed - stromal, BVs
Pharmacological SANCTUARY due to chaotic BVs
HYPOXIC areas - affects action of some drugs

Question 8

Name the 5 CLASSES of how resistance arises

Answer 8

DAILO

1. Inadequate IC concentrations
2. Loss of TARGET protein
3. ⬆️DNA repair
4. ⬇️Apoptosis
5. Other

Question 9

Name 4 steps at which IC drug conc can be decreased

Answer 9

1. Influx
2. Efflux
3. Enzymatic activation
4. Enzymatic degradation

Question 10

Why do many tumors OVERexp some inward transporters?

Answer 10

To SCAVENGE nutrients

Question 11

How does resistance arise at influx step?

Answer 11

Transporters may be ABSENT or INACTIVE

Question 12

Give examples of drugs that need specific INWARD transporters?

Answer 12

Ara-C (Nucleotide transporter)
Cisplatin (Cu transporter)
Nitrogen mustard (Choline transporter)

Question 13

How do some cells develop ONE-STEP resistance to drugs with widely VARIABLE structures

Answer 13

P-glycoprotein transporter (ABC family)

Question 14

What is the NATURAL function of P-glycoprotein transporters

Answer 14

ATP-dependent removal of TOXINS (esp. intestinal epi cells)

Question 15

How do tumor cells use P-glycoprotein to create resistance?

Answer 15

UP-regulated into tumor cells to remove DRUGS

Question 16

Examples of drugs pumped out by P-glycoprotein transporters?

Answer 16

Paclitaxel
Etopisides
Doxorubicin

Question 17

How does degradation of drugs cause resistance?

Give examples

Answer 17

Up-regulation of endogenous degradation enzymes

DPD for 5-FU
Cytidine deaminase for Ara-C

Question 18

Name drugs that need enzymatic ACTIVATION?

How can this lead to resistance

Answer 18

Ara-C needs cytidine KINASE

Resistance = ABSENT activating enzyme

Question 19

3 Tx-approaches to overcome IC drug conc resistance mechanisms

Answer 19

EEE
Engage - combo of pump-inhibitors AND drug
Evade - use drugs that BYPASS EFFLUX
Exploid - search for COLLATERAL sensitivity (alternative targets)

Question 20

Example of LOSS of TARGET protein causing resistance
What DRUGS does this affect the function of?
What is a Tx-approach to overcome this?

Answer 20

TopoII deficiency
Prevents activity of doxorubicin, daunorubicin, etopisides

Tx = use ALTERNATIVE drug

Question 21

Explain why ⬆️DNA repair causes resistance

Answer 21

Drugs that cause DNA dmg = activate S-phase checkpoint = APOP

⬆️DNA repair = resistance

Question 22

How to overcome resistance from ⬆️DNA repair

Answer 22

INHIBIT DNA repair

Question 23

How does ⬇️Apoptosis ARISE

Answer 23

Loss of Bak/Bax

Increase Bcl-2/Bcl-XL

Question 24

Tx-approaches to resistance from ⬇️apoptosis

Answer 24

∆BALANCE of apoptotic proteins to FAVOR apoptosis

siRNA/small molecules to bind and INHIBIT Bcl-2

Question 25

Name 5 “other” resistance mechanisms

Answer 25

``` CCCST CC checkpoints Compartmentalisation CSCs Stress/growth signalling TSG inactivation/oncogen activation ```

Question 26

Explain compartmentalisation

Answer 26

Transporters compartmentalise drugs into VESICLES

Question 27

Examples of stress/growth signalling that can cause resistance

Answer 27

PI3K/MAPK signalling

Question 28

What are CSCs?

Answer 28

Cancer Stem Cells | Small popn of cancer cells with the ability to SELF-RENEW and REGEN tumor

Question 29

3 suggested ORIGINS of CSCs?

Answer 29

1. SC undergoes mutation 2. Progenitor undergoes mutation 3. Normal cell undergoes de-differentiation

Question 30

2 models of how CSCs cause resistance

Answer 30

1. INTRINSIC - CSCs resistant to Tx SURVIVE and regen the tumor 2. ACQUIRED - CSCs develop MUTATIONS to regen the tumor

Question 31

Explain how tumor HETEROGENEITY can contribute to resistance

Answer 31

Heterogeneity WITHIN and ACROSS tumors | =some can survive by chance and regen

Question 32

Name PRE-target resistance mechanisms for Cisplatin

Answer 32

Influx - loss/inactive Cu transporter Efflux - up-regulated P-glycoprotein transporter, etc Sequestration by cytoplasmic “scavengers”

Question 33

Name ON-target resistance mechanisms for Cisplatin

Answer 33

⬆️DNA repair of intra-strand x-links, esp by NER | Impaired MMR proteins = KO apoptosis

Question 34

Name POST-target resistance mechanisms for Cisplatin | Cisplatin has created intra-strand x-link already

Answer 34

∆BALANCE of apoptotic proteins to favor SURVIVAL | INC MAPK signalling