Exam 1 lecture 3 Flashcards
What is unique about the action of tamoxifen as compared to fluvestrant
It activates ER in bone
Which of the following is not a hormone responsive cancer type? Prostate, ovarian, breast, endometrial
Ovarian
which of the following drugs is only used in post menopausal setting
Letrozole, tamoxifen, leuprolide, raloxifene`
Letrozole
Which cpd acts directly on AR.
Leuprolide, Abiraterone, Degarelix, enzalutamide
enzalutamide
How do we identify types of mutations and predict drug response?
We take a biopsy and the molecular signature will be what we use to prescribe the medication
How are genomic DNA from lung cancer biopsies tested? what is it looking for?
via PCR to look for a specific mutation in EGFR. If positive undergo anti egfr therapy
Cell signaling is largely driven by the transfer of
Phosphates
WHat is a major source of phosphate that is transferred by kinase to protein
ATP
What are common targets of kinases for phosphorylation
Tyrosine is a common target of several kinases. Serine, threonine and lipids can also be phosphorylated.
What removes phosphates in kinases
Phosphatases
What are the three types of kinase inhibitors
Type 1- bind to active conformation of kinase
Type 2- Bind and stabilize inactive conformation of kinases
Type 3- occupy allosteric pocket outside of ATP binding pocket
difference between competitive inhibitors and covalent inhibitors
competitive inhibitors bind kinase in a reversible fashion and therefore must compete with ATP for binding.
Covalent inhibitors tend to covalently bind with a reactive nucleophile cysteine residue proximal to the ATP binding site, resulting in blockage of ATP side and irreversible inhibition
Which aa is not a target of phosphorylation. Tyrosine, serine, threonine, alanine
Alanine
Name drugs that inhibit EGFR
Gefetinib
Osmertinib
Afatinib
Lapatinib
Tucatinib is preferentially a HER2 inhibitor
What happens when there is a mutation present in EGFR
mutations in EGFR cause receptor to be constitutively active
EGFR signalling induces ______
cell proliferation
EGFR is overexpressed in what percent of human cancers?
25-50%
EGFR overexpression is correlated with
Poor prognosis
What is erlotinib
A small molecule inhibitor of EGFR tyrosine kinase
How does erlotinib work?
competitively inhibits enzyme by binding to the ATP binding site. Inhibition of kinase activity turns off signal to proliferate
What are gefatinib and erlotinib approved for?
Treatment of patients with NSCLC whose tumors have L858R mutations
MOA of afatinib? What does it treat?
MOA- Covalent inhibitor of all ERB receptors. It is approved for treatment of EGFR mutant NSCLC
What causes resistance to gefitinib?
T790M mutation
What is a drug that works in the presence of T790M mutation?
Osimertinib
What happens to HER2 in breast cancer
It is genomically amplified
What does lapatinib treat? MOA?
MOA- small molecule tyrosine kinase inhibitor that blocks HER2 and EGFR signaling reversibly
selective for tx of HER2 (+) breast cancer
SIde effects of lapatinib
Diarrhea, nausea and vomiting. Reversible decline in cardiac function
MOA of tucatinib? What is it selective for? What is it currently approved for?
MOA- small molecule tyrosine kinase inhibitor that preferentially binds HER2.
Selective for treatment of HER2+ breast cancer
approved for 2nd line therapy for tx of advanced breast cancer (along with capecitabine and trastumazab)
adverse reactions of tucatinib and lapatinib compare
Tucatinib adverse reactions appear to be reduced compared to lapatinib due to increased specificity of HER2
Which cpds inhibit EGFR?
Gefitinib, osmertinib, afatinib, lapatinib
What mutation in EGFR confers resistance to 1st and 2nd generation
EGFR inhibitors
T790M
acronyms for AML, FLT3,
What is the correlation between the two
AML- acute myeloid leukemia
FLT3- FMS- like tyrosine kinase
FLT3 mutations are found in 30% of acute myeloid leukemias
What is FLT3 and what do its mutations cause?
FLT3 ligand is a cytokine receptor important for hematopoietic cell survival and cell proliferation.
Mutations lead to increased proliferation and reduced apoptosis
Differentiate between 1st gen FLT3 inhibitors, 2nd gen and Type II inhibitors
1st gen- Midostaurin, broad kinase inhibitors
2nd gen- crenolanib, are more specific
Type II inhibitors- quizartinib, are specific for ITD mutations.
What is the philadelphia chromosome (PH1)? How is it formed? How common is it in myeloid leukemia?
the philadelphia chromosome is a prototype chromosomal translocation
it is formed by joining 5’ portion of Bcr gene with 3’ portion of abl gene. Bcr-abl formed.
The philadelphia chromosome is demonstrable in 95% of chronic myeloid leukemia
Use of Bcr-abl
Bcr-abl drived several proliferation pathways
What type of drug is Imatinib (MOA)? Primary indication of Imatinib? toxicities?
Imatinib is a type II small molecule inhibitor of the abl tyrosine kinase.
Inhibition of Abl tyrosine kinase results in reduced proliferation and enhanced apoptotic cell death in CML and GIST
Primary indication is chronic myeloid leukemia
toxicities- N/v, fluid retention and edema
How long do patients need to be on abl inhibitors?
life long
Ponatinib MOA? What is a notable thing about ponatinib?
Ponatinib is a BCR-abl inhibitor. It can inhibit the gatekeeper mutation T315i that is resistant to all BCR-abl inhibitors.
effective against all major forms of BCR-ABL mytations.
What is ALK?
wild type ALK is a transmembrane receptor tyrosine kinase similar to EGFR.
What happens when ALK fuses with ELM? What does this lead to?
When ALK beocmes inappropriately fused to ELM-4 it becomes cytoplasmic and constituitively active.
This occurs in 6% of non small cell lung cancers
what type of drug is alectinib (MOA)? What does it treat?
Inhibits the tyrosine kinase ALK.
It is indicated for the treatment of patients with anaplastic lymphoma kinase (ALK) positive NSCLC who are intolerant to crizotinib
What other drug is approved from NSCLC drugs that have ALK mutations other than alectinib?
brigatinib
BRAF place in cancer?
In melanoma, there is a specific mutation in BRAF
What type of drug is Dabrafenib? (MOA)
What is it approved to treat? What responds to Dabrafenib? What does not?
Dabrafenib is a 2nd gen BRAF-V600 inhibitor
Approved for treatemnt of BRAF V600 metastatic melanoma and NSCLC patients that test positive for BRAF V600
Colorectal cancer with RAS and BRAF V600 mutations do not respond to Dabrafenib
MOA of trametinib? Limitation of use? Adverse effect?
Trametinib inhibits the kinase activity of MEK 1 and MEK 2. First approved type III allosteric inhibitor.
Limitation of use- MEKINIST is not indicated for the treatment of patients who have received prior BRAF inhibitor therapy
most common adverse effect- rash
What is BTK? What is it important for?
BTK (burtons tyrosine kinase) is important for normal B cells activity and B cell tumor growth.
Name a covalent inhibitor of BTK
ibrutinib
What does BTK treat?
Used primarily in mantle cell lymphoma (MCL) and chronic lymphocytic leukemia (CLL)
What type of drug is acalabrutinib? (MOA) Compare it to ibrutinib?
WHat does it treat?
Acalabrutinib is a 2nd gen covalent BTK inhibitor. It targets Cys 481.
It is more potent and selective than 1st gen ibrutinib.
Indicated for B cell lymphoma (MCL and CLL)
What are the rapamycin analogues also known as? What do they inhibit?
Rapamycin is also known as sirolimus.
Rapamycin inhibits function of mammalian target of rapamycin (mTOR)
What type of kinase is mTOR
mTOR is a serine threonine kinase
how does rapamycin inhibit immune response?
Blocks IL-2 signaling transduction
Everolimus MOA
only inhibits mTORC1 and not mTORC2 which can lead to feedback activation of Akt
What is the use of everolimus?
used in advanced renal carcinoma and also as an immunosuppressive after an organ transplant
Which of the following drugs targets Her2?
a) Sirolimus
b) Alectinib
c) Vemurafinib
d) Tucatinib
tucatinib
