Cell Signaling in Cancer_Edit

Question 1

How many human kinases are there

Answer 1

518

Question 2

The human kinases encode for how many genes

Answer 2

900

Question 3

How many approved kinase inhibitors

Answer 3

66

Question 4

First tyrosine kinase inhibitor

Answer 4

imatinib

Question 5

3 most common driver mutations in lung cancer

Answer 5

• unknown
• KRAS
• EGFR

(other smaller mutations: EML4-ALK, BRAF, PIK3CA, MET, ERBB2, MAP2K1, NRAS)

Question 6

Major source of phosphate group that is going to be transferred by a kinase to a target protein

Answer 6

adenosine triphosphate (ATP)

Question 7

Describe Type I Kinase Inhibitor

Answer 7

inhibitors bind to the active conformation of the kinase with the aspartate residue (white backbone) of the DFG motif pointing into the ATP-binding pocket.

Question 8

Describe Type II Kinase Inhibitor

Answer 8

inhibitors bind and stabilize the inactive conformation of the kinase with the flipped aspartate residue facing outward of the binding pocket.

Question 9

Describe Type III Kinase Inhibitor

Answer 9

inhibitors occupy an allosteric pocket outside of the ATP-binding pocket.

Question 10

Describe Competitive Inhibitors

Answer 10

bind kinase in a reversible fashion and therefore must compete with ATP for binding.

Question 11

Describe Covalent Inhibitors

Answer 11

tend to covalently bind with a reactive nucleophilic cysteine residue proximal to the ATP-binding site, resulting in the blockage of the ATP site and irreversible inhibition

Question 12

Gefitinib is what type of inhibitor

Answer 12

Type 1 TKI

Question 13

Gefitinib blocks

Answer 13

EGFR

Question 14

Erlotinib blocks

Answer 14

EGFR

Question 15

Gefitinib and Erlotinib approved for

Answer 15

the tx of metastatic non-small cell lung cancer (NSCLC) whose tumors have EGFR exon 19 or exon 21 (L858R) mutations

Question 16

Afatinib blocks

Answer 16

ErbB (EGFR)

covalent inhibitor

Question 17

Afatinib approved for

Answer 17

the tx of EGFR mutant non-small cell lung cancer (NSCLC) with EGFR mutations

Question 18

Dacomitinib blocks

Answer 18

EGFR

covalent inhibitor

Question 19

Dacomitinib approved for

Answer 19

non-resistant EGFR mutant lung cancer

Question 20

Common EGFR Inhibitor SE

Answer 20

rash

associated with a good prognosis

Question 21

What causes resistance to Geftinib

Answer 21

T790M

Question 22

Osimertinib blocks

Answer 22

EGFR

third generation

covalent kinase inhibitor

Question 23

Osimeritinib approved for

Answer 23

pts that acquire the T790M mutation

recent emergence of C797 mutations that abrogate covalent binding

Question 24

Describe relationship between EGFR (ErbB1) and Her2 (ErbB2)

Answer 24

they can form a hetrodimer

Question 25

When do you see Her2

Answer 25

amplified in breast cancer

Question 26

Lapatinib is a

Answer 26

Her2 and EGFR inhibitor reversible inhibitor of both EGFR and Her2

Question 27

Lapatinib is selective for

Answer 27

the tx of Her2+ breast cancer

Question 28

Lapatinib is currently approved with

Answer 28

Capecitabine for the tx of advanced metastatic breast cancer in pts who have progressed on other therapies

Question 29

Neratinib blocks

Answer 29

EGFR more favorable than gefitinib

Question 30

Tucatinib is a

Answer 30

Her2 inhibitor

Question 31

Tucatinib is selective for the tx of

Answer 31

Her2+ breast cancer

Question 32

When use Tucatinib

Answer 32

SECOND line therapy (in COMBINATION with trastuzumab and capaceitabine) for the tx of advanced metastatic breast cancer in pts who have progressed on other therapies

Question 33

Capmatinib is a

Answer 33

MET inhibitor

Question 34

What is MET

Answer 34

receptor for hepatocyte growth factor (HGF)

Question 35

fibroblast growth factor receptor (FGFR) mutationally activated in

Answer 35

bladder cancer

Question 36

platelet derived growth factor receptor (PDGFR) mutationally activated in

Answer 36

gastrointestinal stromal tumors (GIST)

Question 37

rearranged during transfection (RET) becomes mutationally active in

Answer 37

NSCLC and thyroid cancer

Question 38

What is VEGFR?

Answer 38

Vascular Endothelial Growth Factor Receptor critical to tumor angiogenesis currently 7 FDA approved small molecules that inhibit VEGFR

Question 39

What is CML

Answer 39

chronic myelogenous leukemia

Question 40

What happens with CML and what is created

Answer 40

translocation occurs between chromosomes 9 and 22 the rearrangement of genomic material creates a fusion gene called Bcr-Abl that produces a protein (tyrosine kinase) that is thought to promote leukemia

Question 41

What drug blocks the activation of the Bcr-Abl protein

Answer 41

Imatinib (Gleevec)

Question 42

Describe the philadelphia chromosome (Ph1)

Answer 42

is the prototype chromosomal translocation - Formed by joining the 5’-portion of the Bcr gene (chromosome 22) with the 3’-portion of the Abl gene (chromosome 9) - A chimeric transcript is produced, called Bcr-Abl - Chimeric gene is transcribed into a novel 8.5 kb mRNA - RNA translated into a unique 210 kD protein not found in normal cells

Question 43

The Ph1 chromosome is demonstrable in

Answer 43

>95% of CML

Question 44

Imatinib is a

Answer 44

Type II small molecule inhibitor of the Abl tyrosine kinase

Question 45

Inhibition of the Abl tyrosine kinase results in

Answer 45

both reduced proliferation and enhanced apoptotic cell death in CML and GIST

Question 46

Imatinib primary indication

Answer 46

tx of chronic myelocytic leukemia (CML)

Question 47

Ponatinib inhibits

Answer 47

Bcr-Abl

Question 48

Why is Ponatinib notable

Answer 48

It can inhibit the "gatekeeper" mutation T315I that is resistant to all other Bcr-Abl compounds

Question 49

Imatinib and Ponatinib bind Bcr-Abl in the

Answer 49

"DFG out" confirmation

Question 50

Acalabrutinib inhibits/blocks

Answer 50

BTK also targets Cys481 covalent inhibitor

Question 51

Acalabrutinib indicated for

Answer 51

B-cell lymphoma (Mantle cell)

Question 52

What is a significant driver event in lung cancer

Answer 52

EML4-ALK translocation

Question 53

Describe ELM4-ALK translocation

Answer 53

- Wild type ALK is a transmembrane receptor tyrosine kinase similar to EGFR. - When ALK becomes inappropriately fused to ELM4 (or other genes) it become cytoplasmic and constitutively active. - Occurs in 6% of non-small cell lung cancers

Question 54

Alectinib inhibits

Answer 54

ALK (anaplastic lymphoma kinase)

Question 55

Alectinib indicated for

Answer 55

the tx of patients with ALK+, metastatic non-small cell lung cancer (NSCLC) who have progressed on or are intolerant to crizotinib

Question 56

Brigatinib inhibits

Answer 56

ALK

Question 57

Brigatinib approved to treat

Answer 57

NSCLC that have ALK mutations

Question 58

Type of mutation with melanoma

Answer 58

BRAF mutation

Question 59

Dabrafenib blocks/inhibits

Answer 59

BRAF second generation

Question 60

Dabrafenib approved for use

Answer 60

in combination with trametinib for the tx of BRAF V600E/K-mutant metastatic melanoma activation of wild type BRAF remains a problem, combination with trametinib seems to stem induction of squamous cell carcinomas

Question 61

Trametinib blocks

Answer 61

MEK1 and MEK2 first approved Type III allosteric inhibitor

Question 62

Trametinib indicated

Answer 62

in combination with dabrafenib

Question 63

Trametinib NOT indicated for the tx of

Answer 63

pts who have received prior BRAF inhibitor therapy

Question 64

What is PI3K?

Answer 64

Phosphoinositide 3-kinase lipid kinase that leads to downstream activation of protein kinase B (PKB/AKT) --> a pathway critical for cancer cell survival toxicity is a major issue for these compounds

Question 65

Alpelisib is a

Answer 65

lipid kinase inhibitor in breast cancer there are 4 isoforms of PI3K; the alpha isoform is mutationally activated in breast cancer alpelisib is specific for the alpha isoform

Question 66

What mutations drive the indication for Alpelisib?

Answer 66

PIK3CA mutations

Question 67

Name 4 rapalogs

Answer 67

1. Sirolimus 2. Temsirolimus 3. Everolimus 4. Deforolimus

Question 68

Rapamycin is also known as

Answer 68

sirolimus

Question 69

Rapamycin analogues inhibit the function of

Answer 69

mTOR (mammalian target of rapamycin)

Question 70

mTOR is a

Answer 70

serine-threonine kinase

Question 71

What does rapamycin do?

Answer 71

inhibits immune response by blocking IL-2 signaling transduction

Question 72

Everolimus inhibits

Answer 72

mTORC1 and NOT mTORC2 which can lead to feedback activation of Akt

Question 73

Everolimus approved for

Answer 73

the tx of advanced renal carcinoma in pts who have failed sunitinib or sorafenib

Question 74

What is one of the goals of using rapamycin analogues

Answer 74

this "targeted" therapy is to decrease the use of toxic chemotherapies targeting of one aspect/pathway involved in cell growth is not likely to produce a durable response