Kinase inhibitors Flashcards
What is unique about the action of the Tamoxifen as compared to Fluvestrant?
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
d. It activates ER in bone
Fluvestrant degrades ER
Which of the following is not a hormone responsive cancer type?
a. Breast cancer
b. Ovarian cancer
c. Prostate Cancer
d. Endometrial cancer
d. Endometrial cancer
Which of the following is only used in the postmenopausal setting?
a. Letrozole
b. Tamoxifen
c. Leuprolide
d. Raloxifene
a. Letrozole
Which compound acts directly on AR?
a. Leuprolide
b. Abiraterone
c. Degarelix
d. Enzalutamide
d. Enzalutamide
signal transduction through _______ drives proliferation in cancer
kinases
kinases work on ________ factors which change genes
transcription
there are __#___ human kinases & more than ___#__ genes encoding potential kinases
There are currently __#__ approved kinase inhibitors all with a diverse structure
518; 900
~81
kinase inhibitors require _____ to guide their application.
what are the 2 main driver mutations in lung cancer
biomarkers
EGFR & KRAS
Diagnostic Molecular pathology:
Genomic ____from lung cancer biopsies are tested via PCR for a particular mutation of _____.
If positive these patients will go on anti-_____ therapies.
DNA; EGFR; EGFR
EGFR= epidermal growth factor
cell signaling is largely driven by the transfer of ___________
phosphates
what is the major source of the phosphate group that is transferred by a kinase to a target protein?
Adenosine triphosphate (ATP)
__________ is a common target of several kinases.
______ + __________+ _________ can also be phosphorylated. This leads to dimerization and cascade
tyrosine
serine. threonine, lipids
______ are prime targets for small molecule inhibitors
kinases
kinases are generally made up of __ and ____ lobes connected by a hinge region.
an _______ loop controls controls access to the active site
N & C lobes
activation
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 of the ATP-binding pocket.
active
inactive
allosteric
Competitive Inhibitors bind kinase in a __reversible/irreversible__ fashion and therefore must compete with ATP for binding.
reversible
________Inhibitors tend to covalently bind with a reactive nucleophilic _______residue proximal to the ATP-binding site, resulting in the blockage of the ATP site and
_______ inhibition.
covalent; cysteine residue; irreversible
Which amino acid is not a target of phosphorylation?
a. Tyrosine
b. Serine
c. Threonine
d. Alanine
d. Alanine
only has a methyl group
What is the source of the phosphate the gets transferred onto a substrate by a kinase?
a. SAM
b. DNA
c. RNA
d. ATP
d. ATP
EGFR targeted kinase inhibitors
-Mutations in EGFR cause the receptor to be constitutively ___inactivated/activated___.
-Patients with these mutations show an enhanced response to EGFR inhibitors.
activated
what is the main Type 1 (EGFR) targeted kinase inhibitor? what type of cancer is it used to treat
Gefitinib
>largely being replaced by more favorable covalent inhibitors (Afatinib and Neratinib)
EGFR-mutant metastatic NSCLC
Gefitinib (IRESSA - EGFR kinase inhibitor)
> EGFR signaling induces cell proliferation
> EGFR is __under/over___expressed and has higher signaling activity in __%___ of human cancers
> EGFR overexpression correlates with poor prognosis
> Erlotinib is a small molecule __reversible/irreversible__inhibitor of EGFR tyrosine kinase
-Competitively inhibits the enzyme by binding to the ____ binding site in the kinase domain
-Inhibition of kinase activity turns off signal to proliferate
> Gefitinib and Erlotinib are approved for treatment of patients with __________ cancer whose tumors have EGFR exon ____ or _____mutations.
> Drugs are well tolerated – most adverse effects (fatigue, rash, diarrhea).
over; 25-50%
reversible; ATP
metastatic non-small cell lung cancer (NSCLC)
19 or exon 21 (L858R)
afatinib (gilotrif) is a _________ inhibitor of all ___ receptors
tx of _____________ cancer with EGFR mutations
covalent; ErbB
EGFR mutant Non-small cell lung cancer (NSCLC)
> Dacomitinib also a covalent inhibitor approved for non-resistant EGFR mutant lung cancer.
t/f EGFR inhibitor-associated skin rash is normal
true, it means it’s working and pt is more likely to respond to inhibitor
NEED TO KNOW THIS SIDE EFFECT
EGFR inhibitors = RASH
_____ causes resistancce to Geftinib.
______ is used in pts with this mutation
Osimertinib
Osimertinib is a _____ generation EGFR inhibitor. It is a ________ kinase inhibitor.
new reports of ______mutation that abrogates binding –> osimertinib no longer effective
third; covalent; C797
Are EGFR inhibitors curative?
no, pt will be taking them forever
EGFR (ErbB1) forms _______ with HER2 (ErbB2).
heterodimer
_____ is amplified in breast cancer
HER2
Lapatinib (Tykerb):
Small molecule tyrosine kinase inhibitor that blocks HER2 and EGFR signaling
Selective for the treatment of ______ breast cancer
Currently approved (in combination with _________) for the treatment of advanced __non metastatic/metastatic____ breast cancer in patients who have progressed on other therapies
A __________inhibitor of both EGFR and HER2
Common side effects include diarrhea, nausea and vomiting
Reversible decrease in cardiac function – watch for symptoms of _______________
HER2+
capecitabine
metastatic
reversible
congestive heart failure (CHF)
neratinib, dacomitinib & afatinib are are similar to _______but have different indications
lapatinib
Tucatinib (tukysa)
Small molecule tyrosine kinase inhibitor that preferentially binds ____
Selective for the treatment of _____ breast cancer
Currently approved as a ______line therapy (in combination with ______ and _________) for the treatment of advanced metastatic breast cancer in patients who have progressed on other therapies.
Adverse recations appear to be __increased/reduced___compared to lapatinib or the covalent pan-ErbB inhibitors. Potentially due to increased specificity for HER2.
HER2
HER2+
second line
trastuzumab and capecitabine
reduced
Which compounds inhibit EGFR?
a. Gefitinib
b. Osmertinib
c. Afatinib
d. Lapatinib
e. All of the above
e. All of the above
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
what drug was made as a 3rd generation to target this?
d. T790M
osimertinib
______ mutations are found in 30% of acute myeloid leukemia either in internal tandem duplication (ITD-more common) or activating mutation in the tk domain (less common)
a. L858R
b. Exon 19 deletion
c. Exon 14 deletion
d. T790M
e. FLT3
e. FLT3
increases dimerization of receptors which activate the kinase. NOT a point mutation like EGFR inhibitors
The _______ ligand is a cytokine receptor important for hematopoietic cell survival & proliferation
FLT3
First generation FLT3 inhibitors are broad kinase inhibitors –> ___drug name______
Second generation FLT3 inhibitors are more specific –> __drug name__
Type II inhibitors are specific for ITD mutations (30% of AML) –> __drug name__
midostaurin (type I)
crenolanib (type I)
Quizartinib (type II)
Quizartinib is specific for what kind kind of mutations
ITD mutations
Quizartinib is a type II inhibitor (FLT3 inhibitors)
which generation of FLT3 inhibitors are more toxic?
1st gen –> midostaurin
t/f Vascular Endothelial Growth Factor Receptor (VEGFR) is driven by molecular diagnostics
false; not driven by molecular diagnostics
t/f Capmatinib is a MET inhibitor
true
Chromosomal Translocations:
Philadelphia chromosome (Ph1) 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 __#__)
A chimeric transcript is produced, called Bcr-Abl
Chimeric gene is transcribed into a novel 8.5 kb ______
RNA translated into a unique 210 kD protein not found in normal cells
The Ph1 chromosome is demonstrable in ~____% of chronic myeloid leukemia
22
9
mRNA
95
philadelphia chromosome is demonstrable is what kind of cancer?
chronic myeloid leukemia
why is the chimeric transcript that is produced by philadelphia chromosome translocation, Bcr-Abl, so bad?
drives proliferation in several pathways
the chimeric protein is constitutively active which results in malignancy
t/f Abl protein is a tyrosine kinase
true
What does imatinib (Gleevec) target?
Abl tyrosine kinase inhibition
Imatinib (Gleevec) is a Type ___ small molecule inhibitor of the Abl tyrosine kinase
Inhibition of the Abl tyrosine kinase results in both reduced proliferation and enhanced apoptotic cell death in __cancer__ and ___cancer___
Primary indication is in the treatment of _____cancer___
Toxicities:
-Nausea and vomiting common
-Fluid retention and edema
-Neutropenia and thrombocytopenia frequent but mild
type II
CML and GIST
chronic myeloid leukemia (CML)
do pts take imatinib and other abl inhibitors short term or long term
long term - for life
resistance is a lifelong battle!
what does ponatinib (iclusig) inhibit? What specifc gatekeeper mutation does it inhibit?
BCR-Abl
mutation T315I that is resistant to all other BCR-Abl compounds
___________ translocation is a significant driver event in lung cancer (6% of NSCLC)
EML 4-ALK
wild type ALK is a transmembrane receptor tk similar to EGFR that fuses w ELM4 causing it to become active
Alectinib
More specific inhibitor of _____
Requires a ______diagnostic test for the ______ gene
Indicated for the treatment of patients with ______-positive, metastatic non-small cell lung cancer (NSCLC) who have progressed on or are intolerant to ________. This indication is approved under accelerated approval based on tumor response rate and duration of response.
Brigatinib also recently approved NSCLC that have ALK mutations.
ALK-anaplastic lymphoma kinase
companion, fusion
anaplastic lymphoma kinase (ALK)
crizotinib
most melanomas have ______ mutations which activates kinase pathways & self proliferation
Braf
DabRAFenib is a __________ generation BRAF-600 inhibitor for tx of BRAF V600E/K mutatnt metastatic melanoma
used in combo with _________
__________ cancer commonly has Ras & BRAF-V600 mutations by they do not respond to DabRAFenib.
Can be used in NSCLC patients that are ___+ or -____ for BRAF-600 mutations
second
tramatenib
colorectal
+
Trametinib inhibits the kinase activity of _____ and ____
it is a type ____ _____ kinase inhibitor
it is not indicated for tx of pts who have received prior ____ inhibitor therapy
what side effects are common?
MEK1 and MEK2
III allosteric
BRAF
rash, diarrhea, lymphedema
Bruton’s Tyrosine Kinase (BTK) is importnat for normal __ cell activity & ___ cell tumor growth
ibrutinib is a _______ inhibitor of BTK
B cell
covalent
BTK (Bruton’s tyrosine kinase) inhibitors are primarily used in ____ and ___
MCL & CLL (B cell cancers)
_________ is a 2nd gen covalent BTK inhibitor that is more potent & selective than 1st gen, ibrutinib & is also indicated for B-cell lymphoma (MCL & CLL)
acalaBRUTinib
Rapamycin is also known as ________. Rapamycin analogues inhibit the function of ________. It also inhibits immune response by blocking ______ signal transduction
sirolimus; mammalian target of rapamycin (mTOR); IL-1
mTOR is a ______-________ kinase
serine-threonine
Sirolimus & Everolimus only inhibit ______ and not mTORC2 which can lead to feedback activation of ____
mTORC1; akt
_________ is a major problem with kinase inhibitors. However, the main goal kinase inhibitors is the decrease the use of toxic ________
resistance; chemotherapies
Genomic DNA from lung cancer biopsies are tested via PCR for particular mutation of EGFR, if + pts go on anti-EGFR therapies. This is an example of __diagnostic or prognostic___ molecular pathology
diagnostic
t/f oncotype dx helps predict recurrence & therefore can prevent over tx and can drive indications for specific therapies
false; CAN NOT drive indications for specific therapies
can only predict how a pt may respond to tx and help determine why some pts develop metastasis over others
Which of the following drugs targets Her2?
a. Sirolimus
b. Alectinib
c. Vemurafinib
d. Tucatinib
d. Tucatinib
Which of the following drugs targets a kinase that is produced by formation of the Philadelphia chromosome?
a. Alectinib
b. Gefitinib
c. Imatinib
d. binimetinib
c. Imatinib
Which compound below is not a covalent kinase inhibitor?
A. Gefitinib B. Osimertinib C. Afatinib D. Acalabrutinib
A. Gefitinib
Which type of kinase inhibitor can bind in the ATP binding site and stabilize the inactive confirmation of a kinase?
A. Type I B. Type II C. Type III D. Type IV
B. Type II
A CML patient initially tested positive for the Philadelphia chromosome and has enjoyed a 5-year response to imatinib. Unfortunately, the disease has recurred and now tests positive for a T315I mutation.
> Describe how T315I prevents the efficacy of imatinib? (1 sentence)
> What might the next course of BCR-Abl-targeted therapy might include?
resistance occurs overtime, & it prevents imatinib from binding to Bcr-Abl
Ponatinib
