Exam 1 - Oncology (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
which of the following is not a hormone responsive cancer type?
a. breast
b. ovarian
c. prostate
d. endometrial
b. ovarian
which of the following is used only 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
molecular causes of cancer
cancer is a breakdown of cellular maintenance that may be manifested by several causes
signal transduction through kinases drives proliferation
do better therapeutic agents target one kinase pathway or multiple?
multiple
kinases are _____
highly abundant proteins
9 tyrosine kinase inhibitors
imatinib
ibrutinib
dasatinib
ceritinib
lenvatinib
tofacitinib
ruxolitinib
lapatinib
pazopanib
4 serine/threonine kinase inhibitors
palbociclib
trametinib
vemurafenib
dabrafenib
2 dual protein kinase inhibitors
regorafenib
sorafenib
do kinase inhibitors have diverse or similar structures
diverse
genomic DNA from lung cancer biopsies are tested via ____ for a particular mutation of EGFR
if positive, these pts will go on ______ therapies
PCR, anti-EGFR
substrate for every kinase
ATP
what makes tyrosine a good (and common) target of several kinases?
can be phosphorylated at -OH group
other targets of kinases
serine, threonine, and lipids
cell signaling is ____ (complex or simple)
complex
describe the general structure of kinases
N and C groups connected by a hinge region
activation loop controls access to the active site
3 types of kinase inhibitors and differences btwn them
type 1: bind to active conformation of kinase
type 2: bind and stabilize the inactive conformation of kinase
type 3: occupy an allosteric pocket outside of the ATP-binding pocket
competitive vs. covalent inihbitors
competitive inhibitors compete with ATP in a reversible fashion
covalent is irreversible (stronger bond)
which amino acid is not a target of phosphorylation?
a. tyrosine
b. serine
c. threonine
d. alanine
d. alanine (only has methyl side group, not as reactive)
what is the source of the phosphate that gets transferred onto a substrate by a kinase?
a. SAM
b. DNA
c. RNA
d. ATP
d. ATP
most commonly mutated growth factor in lung cancer
EGFR
T/F: Gefitinib. requires genetic test before prescribing
T
Gefitinib and Erlotinib indication
EGFR mutant metastatic NSCLC
Gefitinib (IRESSA) and Erlotinib fxn thru ____ kinase activity
tyrosine
EGFR signaling induces cell ____. inhibition of kinase activity turns ___ signal to _____
proliferation, off, proliferate
AE of Gefitinib and Erlotinib
fatigue, rash, diarrhea
Afatinib (Gilotrif) indication
EGFR mutant NSCLC
Afatinib (Gilotrif) is what type of inhibitor
covalent inhibitor of all ErbB receptors
Explain how EGFR inhibitor associated skin rash can be a good thing
If rash seen (normally on chest/neck area), pts tend to respond better to therapy and live longer
T790M mutation is associated with drug _______ (resistance or sensitivity)
resistance (this one specifically causes resistance to Gefitinib)
L858R is commonly associated with drug _______ (resistance or sensitivity)
sensitivity
drug to give pt if T790M mutation found
Osimertinib (third gen. EGFR inhibitor)
type of bond Osimertinib forms
covalent
Lapatinib (Tykerb) MOA
small molecule tyrosine kinase inhibitor that blocks HER2 and EGFR signaling
Lapatinib (Tykerb) indication
approved (in combo with capecitabine) for tx of advanced metastatic breast cancer in pts whose cancer has progressed on other therapies
Lapatinib (Tykerb) bond (and what it binds to)
reversible inhibitor of EGFR and HER2Lapatinib (Tykerb) indication
Lapatinib (Tykerb) is selective for HER2 or EGFR?
HER2
SE of Lapatinib (Tykerb)
NVD
- watch for sx of CHF too
Tucatinib (Tukysa) use
for tx of HER2+ breast cancer
-2nd line therapy
FLT3 inihibitors
-1st gen: ______ is _____ kinase inhibitor
midostaurin is broad
FLT3 inihibitors
-2nd gen: ______ is _____ kinase inhibitor
crenolanib is more specific
FLT3 inihibitors
-type 2: ______ is _____ kinase inhibitor
Quizartinib is specific for ITD mutations
Imatinib (Gleevec) MOA and reasoning
type 2 small molecule inhibitor of the Abl tyrosine kinase. activity of Bcr-Abl chimeric protein is constitutively active which results in malignancy
-primarily treats CML
Imatinib (Gleevec) AE
N/V
fluid retention and edema
neutropenia and thrombocytopenia frequent but mild
resistance is constant battle
Ponatinib (Iclusig) use
BCR-Abl inhibitor effective against all major mutant forms of BCR-Abl
drug approved for ALK mutation in NSCLC who have progressed or are intolerant to crizotinib
Alectinib (Alecensa)
Trametinib (Mekinist) MOA
inhibits kinase activity of MEK1 and MEK2
-type 3 inhibitor
cannot use what drug if pt has history of BRAF inhibitor therapy
trametinib
Trametinib (Mekinist) AE
rash
diarrhea
lymphedema
Acalabrutinib
2nd gen covalent BTK inhibitor
-more potent and more selective than 1st gen ibrutinib
-indication is B cell lymphoma (MCL and CLL)
rapamycin analogues
-aka: Sirolimus
-mTOR is a serine-threonine kinase
-inhibits immune response by blocking IL-2 signaling tranduction
T/F: Everolimus inhibits mTORC1 and mTORC2
F, only mTORC1
biggest problem with kinase inhibitors
resistance
-they are not curative therapy
