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864 > Kinases > Flashcards

Kinases Flashcards

1
Q

what is unique about the action of tamoxifen as compared to fulvestrant
a) it leads to ER degradation
b) it holds ER out of the nucleus
c) it ejects ER from the cell
d) it activates ER in bone

A

it activates ER in bone

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2
Q

which of the following is not a hormone responsive cancer type
a) breast
b) ovarian
c) prostate
d) endometrial

A

ovarian

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3
Q

which of the following is a non-steroidal aromatase inhibitor?

A

A

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4
Q

which of the following is only used in the post menopausal setting?
a) letrozole
b) tamoxifen
c) leuprolide
d) raloxifene

A

letrozole

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5
Q

which compound acts directly on AR?
a) leuprolide
b) abiraterone
c) degarelix
d) enzalutamide

A

enzalutamide

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6
Q

kinases are highly prevalent molecules

signal transduction through kinases drives ___

over 518 human kinases and more than 900 genes encoding kinases have been identified

currently 81 approved kinase inhibitors

A

proliferation

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7
Q

T or F: kinase inhibitors have diverse structure

A

T
- structures are kinda similar to ATP but not really

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8
Q

as targeted therapies, kinase inhibitors require ___ to guide their application

A

biomarkers

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9
Q

diagnostic molecular pathology

___ ___ from lung cancer biopsies are tested via PCR for a particular mutation of EGFR
- if positive, these patients will go on anti-EGFR therapies

A

genomic DNA

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10
Q

cell signaling is driven by phosphate transfer

___ is the major source of the phosphate group that is going to be transferred by a kinase to a target protein

A

ATP

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11
Q

___ is a common target of several kinases

___ , threonine, and ___ can also be phosphorylated

A

tyrosine
serine
lipids

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12
Q
  • ___ balance the activity of kinases by removing phosphates
  • kinases better understood and are prime targets for small molecule inhibitors
A
  • phosphatases
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13
Q

types of kinase inhibitors

  • Type I inhibitors bind to the ___ conformation of the kinase
  • Type II inhibitors bind and stabilize the ___ conformation of the kinase
  • Type III inhibitors occupy an ___ pocket outside the ATP binding pocket

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

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

A
  • active
  • inactive
  • allosteric
  • competitive
  • covalent, cysteine
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14
Q

Which amino acid is not a target of phosphorylation
a) tyrosine
b) serine
c) threonine
d) alanine

A

alanine

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15
Q

what is the source of the phosphate that gets transferred onto a substrate by a kinase
a) SAM
b) DNA
c) RNA
d) ATP

A

ATP

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16
Q

EGFR targeted kinase inhibitor

  • mutations in EGFR cause kinase to be ___ active
  • patients with these ___ response to EGFR inhibitors
  • gefitinib is being replaced by more favorable ___ inhibtiors (Afatinib and Neratinib)
A
  • constitutively
  • enhanced
  • covalent
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17
Q

Gefitinib (IRESSA)

  • epidermal growth factor receptor (EGFR) functions through tyrosine kinase activity
  • EGFR signaling induces cell ___

Erolotinib is a small molecule reversible inhibitor ___ kinase
- ___ inhibits the enzyme by binding to the ___ binding site
- Gefitinib and erlotinib are approved for treatment of patients with metastatic NSCLC whose tumors have EGFR exon __ or ___
- drugs are well tolerated - fatigue, rash, diarhhea

A
  • proliferation
  • tyrosine
  • competitively, ATP
  • 19, 21
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18
Q

Afatinib (Gilotrif)

  • ___ inhibitor of all ErbB receptors
  • approved in 2013 for treatment of NSCLC with EGFR mutations
  • at the same time, FDA approved the therascreen for detection of exon ___ and ___
  • Dacomitinib is also a ___ inhibitor approved for non-resistant EGFR mutatn lung cancer
A
  • covalent
  • 19, 21
  • covalent
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19
Q

a rash can be a good thing

T or F: EGFR inhbitor associated skin rash means that they will have a good response and survive a lot longer

A

T

20
Q

___ causes resistance to Geftinib

A

T790M

21
Q

___ is essentially a new key to fit the change in the lock that occurs upon acquisition of the T790M mutation

A

osimertinib

22
Q

osimertinib (Tagrisso)

  • a ___ generation EGFR inhibitor
  • ___ kinase inhibitor
  • effective against ___ mutant EGFR
  • recent studies are reporting emergence of C797 mutations that abrogates covalent binding
A
  • 3rd
  • covalent
  • T790M
23
Q
  • EGFR (ErbB1) forms a heterodimer with ___ (ErbB2)
  • ___ is genomically ___ in breast cancer
A
  • HER2
  • HER2, amplified
24
Q

Lapatinib (Tykerb)

  • small molecule ___ kinase ___ inhibitor that blocks ___ and ___ signaling
  • selective for treatment of ___ + breast cancer
  • currently approved (in combo with ___) for the treatment of advanced metastatic breast cancer in patients who have progressed on other therapies
  • SE: diarrhea, N/V, reversible decrease in ___ function (watch for symptoms of CHF)
A
  • tyrosie, reversible, EGFR, HER2
  • HER2
  • capecitabine
  • cardiac
25
Q

Tucatinib (Tukysa)

  • small molecule tyrosine kinase inhibitor that preferentially binds ___
  • currently approved (in combo with ___ and ___ ) for the treatment of advanced metastatic breast cancer in patients who have progressed on other therapies
  • reduced adverse reactions compared to lapatinib or covalent pan-ErbB inhibitors - potentially due to increased specificity for ___
A
  • HER2
  • trastuzumab, capecitabine
  • HER2
26
Q

which compounds inhibit EGFR?
a) gefitinib
b) osmertinib
c) afatinib
d) lapatinib
e) all of the above

A

all of the above

27
Q

what mutation in EGFR confers resistance to 1st and 2nd generation EGFR inhibitors
a) L858R
b) exon 19 deletion
c) exon 14 deletion
d) T790M

A

T790M

28
Q

fms-like tyrosine kinase 3 (FLT3) in AML

  • FLT3 mutations are found in 30% of AML
  • either internal tandem duplication (ITD) (common) or activating mutation in tyrosine kinase domain (rare)
  • FLT3 ligand is a cytokine receptor important for ___ cell survival and proliferation
  • mutations lead to increased ___ and decreased ___
A
  • hematopoietic
  • proliferation, apoptosis
29
Q

FLT3 inhibitors

  • 1st gen FLT3 inhibitors (midostaurin) are ___ kinase inhibitors
  • 2nd gen FLT3 inhibitors (crenolanib) are more __
  • type II inhibitors (quizartinib) are specific for ___ mutations
A
  • broad
  • specific
  • ITD
30
Q

other receptor kinase inhibitors driven by molecular diagnostics

  • MET is the receptor for hepatocyte growth factor (HGF), which can become constitutively activated through the loss of exon ___ in a small % of NSCLC. ___ is a MET inhibitor
  • Fibroblast growth factor receptor (FGFR); mutationally activated in bladder cancer = ___ and cholangiocarcinoma = ___ and ___
  • platelet derived growth factor receptor (PDGFR); mutational activated in gastrointestinal stromal ___
  • rearranged during tranfection (RET) becomes mutationally active in MSCLC and thyroid cancer = ___
A
  • 14
  • capmatinib
  • erdafitinib, pemigatinib, infigratinib
  • avapritinib
  • selpercatinib
31
Q

other receptor kinase inhibitors NOT driven by molecular diagnostics

  • in addition to directly driving tumor cell growth, VEGFR is aso critical to tumor angiogenesis
  • limited impact on disease: 9 FDA approved drugs ( ___ ) that inhibit several RTKs
A
  • sunitinib
32
Q

Translocation of Bcr-Abl Genes

  • fusion protein with ___ ___ activity
A

tyrosine kinase

33
Q

chromosomal translocations

  • Philadelphia chromosome is the prototype chromosomal translocation
  • formed by joining the 5’-portion of the Bcr gene (chromosome __ ) with the 3’-portion of the Abl gene (chromosome __ )
  • chimeric transcript is produced (Bcr-Abl)
  • RNA translated to unique 210 kD ___ not found in normal cells
  • Philadelphia chromosome demonstrable in 95% of chronic ___ leukemia
  • drives several ___ pathways
A
  • 22, 9
  • protein
  • myeloid
  • proliferation
34
Q

Imatinib (Gleevec)

  • the ___ protein is a tyrosine kinase
  • Bcr-Abl chimeric protein is ___ active, resulting in malignancy
  • Gleevec is a Type __ small molecule inhibitor of the Abl tyrosine kinase
  • inhibition results in both reduced proliferation and enhanced ___ in CML and GIST
  • primary indication is in the treatment of ___

toxicities
- N/V
- fluid retention/edema
- ___ and ___ frequent but mild

because patients need to be on Abl inhibitors for life, ___ is a lifelong battle

A
  • Abl
  • constitutively
  • II
  • apoptosis
  • CML
  • neutropenia, thrombocytopenia
  • resistance
35
Q

Ponatinib (Iclusig)

  • ___ inhibitor
  • effective against all the major mutant forms
  • can inhibit “gatekeeper” resistance mutation ___ which is resistant to all other BCR-Abl compounds
A
  • BCR-Abl
  • T315I
36
Q

EML4-ALK translocation

  • significant driver event in ___ cancer
  • ALK is a ___ receptor tyrosine kinase similar to EGFR
  • when ALK becomes inappropraitely fused to ELM4 (or other genes) it becomes ___ and ___ active
  • occurs in 6% of non-small cell lung cancers
A
  • lung
  • transmembrane
  • cytoplasmic, constitutively
37
Q

Alectinib (Alecensa)

  • more specific inhibitor of ___
  • requires a companion diagnostic test for the fusion gene
  • indicated for the treatment ALK positive, metastatice NSCLC who have progressed on/are intolerant to ___ . (Accelerated approval)
  • ___ alsorecently approved NSCLC that have ALK mutations
A
  • ALK
  • crizotinib
  • brigatinib
38
Q

BRAF

mutation in ___

A

melanoma

39
Q

Dabrafenib (Tafinlar)

  • ___ gen BRAF-V600 inhibitor
  • used in combo with ___ for treatment of BRAF V600E/K metant metastatic melanoma
  • activation of wild type BRAF remains a problem, combination with ____ seems to stem induction of squamous cell carcinomas
  • colorectal cancer commonly has Ras and BRAF-V600 mutations, these tumors do not ___ to dabrafenib
  • also approed for NSCLC patints that test positive for BRAF-600 mutations
A
  • 2nd
  • trametinib
  • trametinib
  • respond
40
Q

Trametinib (Mekinist)

  • inhibits the kinase activity of ___ and ___
  • can be used in combo with ___
  • first type ___ allosteric inhibitor
  • limitation of use: Mekinist is NOT indicated for the treatment of patients who have received prior ___ inhibitor therapy
  • most common SE: ___ , diarrhea, lymphedema
  • FDA approved encorafenib and binimetinib (Braftovi and Mektovi) in combo for patients with unresectable or metastatic ___ with BRAF V600E or V600K mutation
A
  • MEK1, MEK2
  • dabrafenib
  • III
  • BRAF
  • rash
  • melanoma
41
Q

BTK in B-cell malignancies

  • BTK is important for normal B cells activity and B cell tumor growth
  • ibrutinib is a ___ inhibitor of BTK
  • used primarily in mantle cell lymphoman (MCL) and chronic lymphocytic leukemia (CLL)
A
  • covalent
42
Q

Acalabrutinib

  • 2nd gen ___ BTK inhibitor
  • also targets ___
  • more potent and more selective than first generation inhibitor, ___
  • indicated for B cell lymphoma (MCL and CLL)
A
  • covalent
  • Cys481
  • ibrutinib
43
Q

Rapamycin analogues

  • Rapamycin, also known as ___
  • inhibit the function of mammalian target of Rapamycin (mTOR)
  • mTOR is a ___ - ___ kinase
  • inhibits immune response by blocking ___signaling transduction
  • originally developed as an antifungal but failed in this capavity and was pursued as an anticancer agent
A
  • serine-threonine
  • IL-2
44
Q

everolimus (Afinitor)

  • in addition to oncology, aslso used in organ transplant due to ___ effects
  • approved for treatment of advanced ___ cardinoma in patients who have failed sunitinib or sorafenib
  • only inhibits ___ and NOT mTORC2 which can lead to feedback activation of Akt
A
  • immunosupressive
  • renal
  • mTORC1
45
Q

T or F: resistance is a major problem with kinase inhibtors

A

T

46
Q

molecular pathology

OncotypeDx helps to predict ___ and therefore can prevent over treatment, but these tests do NOT drive indications for specific therapies

A

recurrence

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