oncogene

Question 1

What is oncogenes

Answer 1

gain of function (stuck accelerator)
cell growth and antigrowth signals are always there but if the pro growth signals are stuck then it will always send out the signal
a dominant phenotype

Question 2

What is an oncogenic mutation?

Answer 2

a gain of function of a gene associated with cancer progression

a gain of function that causes cancer

Question 3

What is proto-oncogenes and how do they relate to oncogenes?

Answer 3

promote normal cell divison

mutant forms of proto-oncogenes induce or continue uncontrolled cell division

Question 4

What type of phenotype is oncogenes

Answer 4

dominant mutations

they only require one allele mutation to result in an altered phenotype

Question 5

what are oncogenic mutations?

Answer 5

5 mechanisms

1. point mutation
2. gene amplification
3. chromosomal translocation
4. local DNA rearrangements
5. insertional mutagenesis

Question 6

What is the effect of point mutations on oncogenic proteins?

Answer 6

abnromal (hyperactive) protein (RAS)

Question 7

What is the effect of gene amplification on oncogenic proteins?

Answer 7

excess normal proteins (MYC)

Question 8

What is the effect of chromosomal translocation on oncogenic proteins?

Answer 8

excess normal protein or abnormal (hyperactive) protein (BCR-ABL)

Question 9

What is the effect of local DNA rearrangements on oncogenic proteins?

Answer 9

insertion or deletion or inversion or transposition all create abnormal (hyperactive) proteins

Question 10

What is the effect of insertional mutagenesis on oncogenic proteins?

Answer 10

excess normal protein

Question 11

What do oncogenic RAS do?

Answer 11

they increase RAS activity and increase in proliferation

Question 12

what is the steps of RAS pathway

Answer 12

1. EGF (growth factor) binds to the EGFR (growth factor receptor) and then TK receptors dimerize and recruit phosphates
2. phosphates recruit GRB2 and connect through SH2 domain
3. GRB2 recruits SOS and connects through SH3 domain
4. SOS is a GEF that turns GDP into GTP which helps activate RAS pathway
   (then farnesyl transferase must be added to fully activate RAS)

Question 13

how is RAS activated? what does it have that the inactived doesnt?

Answer 13

RAS GDP = inactive
RAS GTP = active
RAS GTP + farnesyl transferase = fully activated

Question 14

what are the types of RAS and the cancer associated with it?

Answer 14

HRAS
NRAS
KRAS: G12C – lung (NSCLC)
G12D – pancreatic, colorectal

Question 15

what is a common cancer for BCR-ABL?

Answer 15

CML

Question 16

what is a common cancer for myc?

Answer 16

neuroblastoma

Question 17

What occurs when RAS is mutated?

Answer 17

RAS is constitutively active
and mutated RAS cannot hydrolyze GTP into GDP

Question 18

what when MYC is mutated

Answer 18

too many copies
an overproduction of the TF for cell proliferation and cell cycle regulators (CDK and cyclins)

Question 19

what is a therapy for MYC

Answer 19

OMOMYC, it is still in clinical trials

it binds to DNA (EBOX) to block MYC from binding
sequesters/binds to myc itself

Question 20

what happens when BCR-ABL is mutated?

Answer 20

ABL protein
- tyrosine kinase
- nucleal ABL protein has DNA repair functions

BCR-ABL
- constitutively active fushion gene
- segments of 2 different chromosomes exchange to make a new gene
- cytoplasmic BCR-ABL inhibits apoptosis

Question 21

what is a therapy for BCR-ABL

Answer 21

gleevec
it blocks ATP binding site to inactive it

Question 22

why is it difficult for RAS to be undruggable

Answer 22

1. GTP-binding pocket is relatively inaccessible –> hard to access
2. RAS has high affinity for GTP –> hard to develop a competitive inhibitor
3. High levels of cytosolic GTP –> hard to develop a competitive inhibitor

Question 23

What are some therapeutics for RAS?

Answer 23

1. Rigosertib
2. farnesyltransferase inhibitors (FTIS)
3. sotorasib & adagrasib

Question 23

what does rigosertib do?

Answer 23

binds to RAS binding partners (SOS, RAF, PI3K) and this causes RAS activation to decrease

Question 24

what does FTIS do?

Answer 24

prevents localization of RAS to membrane and RAS cannot be fully activated no farnesyl groups

Question 25

what does sotorasib and adagrasib do?

Answer 25

only for G12C KRAS mutations competitive inhibitor that binds to mutated cystine and RAS cannot be converted to RAS-GTP thus KRAS GDP is turned off

Question 26

what are some EGF and what do they do?

Answer 26

HER1: in response to EGF, HER1 will dimerize with itself or form heterodimers with other HERs HER2: overexpressed in some breast cancers when overexpressed results in ligand-independent HER2 dimerization of RAS-MEK or PI3K - Akt pathway

Question 27

what are some breast cancer therapeutics

Answer 27

herceptin letrozole tamoxifen ibrance

Question 28

what does herceptin do?

Answer 28

HER2 receptor monoclonal antibody that blocks binding to HER2 receptors

Question 29

what does letrozole do?

Answer 29

estrogen and progesterone receptors aromatase inhibitor that blocks estrogen production

Question 30

what does tamoxifen do?

Answer 30

estrogen and progesterone receptors small molecule inhibitor of estrogen/progsterone binding to its receptor

Question 31

what does ibrance do?

Answer 31

estrogen and progestrone receptors small molecule that prevents cyclin D from binding CDK 4/6 in G1 --> halts cell cycle

Question 32

what therapeutic should be given if estrogen receptor +, progesterone +, and HER2 +

Answer 32

tamoxifen, decreases the production of estrogen, herceptin

Question 33

what therapeutic should be given if estrogen receptor +, progesterone +, and HER2 -

Answer 33

tamoxifen ibrance

Question 34

what therapeutic should be given if estrogen receptor -, progesterone -, and HER2 +

Answer 34

Herceptin

Question 35

what therapeutic should be given if estrogen receptor -, progesterone -, and HER2 -

Answer 35

its a triple negative and its dangerous no known inhibitor