L5-6 Kinases Flashcards
what do all of the kinase inhibitors bind to?
the ATP-binding site of protein kinases
what AA is a common target of several kinases? (slide 19)
tyrosine
what 3 AAs can be phosphorylated and are substrates for kinases and why
Tyrosine
Serine
Threonine
they all have -OH group
what balances the activity of kinases by removing phosphates?
phosphatases - lol
what common step in cell signaling activates kinase activity?
dimerization of something somewhere idk
Types of kinase inhibitors:
Bind to active conformation of the kinase
A. Type I
B. Type II
C. Type III
A
Types of kinase inhibitors:
Bind and stabilize the inactive conformation of the kinase
A. Type I
B. Type II
C. Type III
B
Types of kinase inhibitors:
Occupy an allosteric pocket outside of the ATP-binding pocket
A. Type I
B. Type II
C. Type III
C
Competitive Inhibitors bind kinase in a ________ fashion and therefore must compete with _______ for binding.
reversible
ATP
What type of TKI is gefitinib?
Type I
where does gefitinib bind?
The ATP-binding site of the TK domain of EGFR
EGFR functions through what?
TK activity
EGFR signaling induces what?
cell proliferation
Erlotinib is a small molecule ________ inhibitor of EGFR tyrosine kinase
Reversible
T or F:
Erlotinib is a competitive inhibitor
True, inhibits the enzyme by binding to the ATP binding site in the kinase domain (of EGFR)
Inhibition of kinase activity turns off what?
the signal to proliferate
Gefitinib and Erlotinib are both approved for patients that fall under what criteria?
NSCLC
EGFR exon 19 or 21 mutations
3 common adverse effects of gefitinib and erlotinib
fatigue
rash
diarrhea
Afatinib is a ______ inhibitor of all ____ receptors
covalent**
ErbB
what is Afatinib approved for?
EGFR mutant NSCLC with EGFR mutations (exon 19 and 21)
What is dacomitinib approved for?
non-resistant EGFR mutant lung cancer
what is the main side effect “we should know” from EGFR inhibitors?
skin rash
what mutation causes resistance to gefitinib?
T790M **
Osimertinib:
- A ___ generation EGFR inhibitor
- ______ kinase inhibitor
- Effective against the ____ mutant EGFR
third
covalent
T790M
EGFR forms a heterodimer with ______
HER2 (ErbB2)
HER2 is genomically _____ in breast cancer
amplified
Lapatinib:
- small molecule TKI that blocks _____ and _____ signaling
HER2
EGFR
Lapatinib:
- selective for the treatment of _______ breast cancer
HER2+.
lapatinib:
- currently approved (in combination with capecitabine) for the treatment of ________ ________ breast cancer in pts who have progressed on other therapies
advanced metastatic (late stages)
T or F:
Lapatinib is an irreversible inhibitor of both EGFR and HER2
false, reversible
3 common side effects of lapatinib
diarrhea
nausea
vomiting
(also watch for sxs of congestive heart failure for some reason)
Tucatinib:
- small molecule TKI that preferentially binds ____
HER2
Tucatinib:
- selective for the tx of _______ ______
HER2+ breast cancer
lapatinib:
- currently approved (in combination with capecitabine and trastuzumab) for the treatment of ________ ________ breast cancer in pts who have progressed on other therapies
advanced metastatic (sorry same card twice kinda minus the trast drug)
Tucatinib has reduced adverse reactions compared to lapatinib, why is this?
since it is more selective for HER2
Which compounds inhibit EGFR?
A. Gefitinib
B. Osmertinib
C. Afatinib
D. Lapatinib
E. All of the above
E
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
D
what the fuck is the FLT3 (fms-like tyrosine kinase 3) ligand?
a cytokine receptor important for hematopoietic cell survival and proliferation
FLT3 mutations are found in 30% of what?
acute myeloid leukemia (AML)
Mutations in FLT3 lead to increased ______ and decreased______
proliferation
apoptosis
1st gen FLT3 inhibitors (midostaurin) are broad ________ _______
kinase inhibitors, no wonder theyre in this deck huh
2nd gen FLT3 inhibitors (crenolanib) are better than 1st gen, but why?
more specific
Type II inhibitors (FLT3 specific) (e.g. Quizartinib) are specific for what? *
ITD (internal tandem duplication) mutations
MET is the receptor for what?
hepatocyte growth factor (HGF)
capmatinib is a _____ inhibitor
MET (my friend wears a METS baseball CAP?)
In addition to directly driving tumor cell growth, Vascular Endothelial Growth Factor Receptor (VEGFR) is also critical to __________ __________making it an attractive target.
tumor angiogenesis
if you see “Bcr-Abl” what should you instantly think about?
philadelphia
Bcr-Abl:
_______ protein with TK activity
fusion
Philadelphia chromosome (Ph1) is the prototype ___________ ____________
chromosomal translocation
The Ph1 chromosome is demonstrable in ~95% of what type of cancer
chronic myeloid leukemia (CML)
T or F:
Bcr-Abl is a chimeric protein
true i guess idk
T or F:
Bcr-Abl is a crucial protein for apoptosis
False, it actually drives several proliferation pathways
if you see Bcr-Abl, what type of cancer should you think of?
CML
T or F:
Bcr-Abl acts as an overexpressed kinase
True (i think the Abl part is a TK)
The kinase activity of the Bcr-Abl protein is _________ active. What does this mean?
Constitutively
constitutive activity results in malignancy **
Imatinib is a Type ____ small molecule inhibitor of the Abl TK
Type II
what does inhibiting the Abl TK result in? (2 things)
reduced proliferation and enhanced apoptosis in CML and GIST
Imatinib primary indication
Treatment of CML
(IM A CHRONIC nib?)
toxicities of imatinib
N/V
edema
neutropenia and thrombocytopenia
so basically, if an exam question says anything about CML whats your next move?
clicking the shit that says Imatinib
Ponatinib inhibits what?
Bcr-Abl, so both components instead of just the one?
T or F:
Ponatinib is effective against ALL the major mutant forms of Bcr-Abl
True, actually
Ponatinib can inhibit the “gatekeeper” ** mutation ______ that is resistant to all other Bcr-Abl compounds
T315
okay here’s the scene. you’re sitting in the exam room. you click to question 33. It says something about T315. What do you do?
SMACK whatever option has Ponatinib
EML4-ALK translocation is significant driver event in what?
lung cancer
what is the ALK part of EML4-ALK?
something about wild type ALK. he is a transmembrane receptor TK similar to EGFR
is EGFR a receptor tyrosine kinase (RTK) ?
yes
When ALK becomes “inappropriately” fused with ELM4, what happens?
it becomes cytoplasmic and constitutively active (which is bad im pretty sure)
What is the significance of ALK becoming cytoplasmic after fusing to ELM4?
it turns on pathways that ALK would not normally turn on
Alectinib MOA-ish
more specific inhibitor of ALK
T or F:
Anaplastic lymphoma kinase (ALK) is a tyrosine kinase
True
T or F:
Alectinib requires a companion diagnostic test for the fusion gene
true
Indication of Alectinib
ALK+ NSCLC who have progressed on or are intolerant to crizotinib
what other drug is an ALK inhibitor that isnt alectinib
Brigatinib
when you see BRAF what cancer do you think of?
boobie
Dabrafenib MOA
2nd gen BRAF-V600 inhibitor
Dabrafenib approved in combo with _______ for tx of BRAF V600E/K-mutant metastatic melanoma
trametinib (I MET this guy and he DABbed me up)
Valine(V) 600E/K is a mutation you see in what? what drug do you use when you see it?
melanoma
Dabrafenib
Trametinib inhibits the kinase activity of ____ and _____
MEK1 and MEK2
Trametinib has a limitation of use, what is it?
pts who have received prior BRAF inhibitor therapy
3 most common AE’s for trametinib
Rash*
diarrhea
lymphedema.
Which type of inhibitor is Trametinib?
A. 1st gen (active site)
B. 2nd gen
C. 3rd gen (allosteric site)
C. allosteric
Encorafenib and Binimetinib (very niche on slide 59) can both be used in combo for pts with what?
UNRESECTABLE or metastatic melanoma with a BRAF V600E. or V600K mutation
Brutons TK (BTK) is important for normal __ cell activity and __ cell tumor growth
B and B
Ibrutinib is a covalent inhibitor of ?
BTK (brutons TK) (woah brut is in the name!)
BTK is commonly associated with what?
sorry this is vague but its B-cell malignancies
BTK inhibitors are used primarily in which 2 cancers
mantle cell lymphoma (MCL)
chronic lymphocytic leukemia (CLL)
2nd gen BTK inhibitor:
A. Ibrutinib
B. Acalabrutinib
B
T or F:
Both ibrutinib and acalabrutinib are covalent BTK inhibitors
True
what is acalabrutinib indicated for?
B-cell lymphoma (MCL and CLL) just like ibrutinib
Acalabrutinib also targets what niche thing?
Cys481
what is rapamycin more commonly known as?
Sirolimus
what do the rapamycin analogs (sirolimus) inhibit?
the fxn of mTOR
wtf is mTOR
a serine-threonine kinase
T or F:
Everolimus inhibits both mTORC1 mTORC2
False, it only inhibits mTORC1
Everolimus has a second therapeutic use that isnt for oncology reasons, what is it?
organ transplants
T or F:
Targeted therapies (kinase inhibitors) avoid many toxicities that other products can cause
true
what kind of DNA is used from lung cancer biopsies to determine drug therapy
GENOMIC
Oncotype Dx helps to predict ________ and therefore can prevent overtreatment, but these tests (do/do not) drive indications for specific therapies
recurrence
do not
