Kinase inhibitors Flashcards by Hannah Eberle

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

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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

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Which of the following is only used in the postmenopausal setting?

a. Letrozole
b. Tamoxifen
c. Leuprolide
d. Raloxifene

a. Letrozole

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Which compound acts directly on AR?

a. Leuprolide
b. Abiraterone
c. Degarelix
d. Enzalutamide

d. Enzalutamide

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signal transduction through _______ drives proliferation in cancer

kinases

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kinases work on ________ factors which change genes

transcription

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there are __#___ human kinases & more than ___#__ genes encoding potential kinases

There are currently __#__ approved kinase inhibitors all with a diverse structure

518; 900

~81

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kinase inhibitors require _____ to guide their application.

what are the 2 main driver mutations in lung cancer

biomarkers

EGFR & KRAS

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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

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cell signaling is largely driven by the transfer of ___________

phosphates

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what is the major source of the phosphate group that is transferred by a kinase to a target protein?

Adenosine triphosphate (ATP)

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__________ is a common target of several kinases.

______ + __________+ _________ can also be phosphorylated. This leads to dimerization and cascade

tyrosine
serine. threonine, lipids

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______ are prime targets for small molecule inhibitors

kinases

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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

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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

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Competitive Inhibitors bind kinase in a __reversible/irreversible__ fashion and therefore must compete with ATP for binding.

reversible

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________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

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Which amino acid is not a target of phosphorylation?
a. Tyrosine
b. Serine
c. Threonine
d. Alanine

d. Alanine

only has a methyl group

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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

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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

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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

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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)

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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.

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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

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_____ 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