Lecture 3 - Kinases Flashcards
Molecular causes of cancer
signal transduction through kinases drives proliferation
Kinases are one of the
largest classes of proteins encoded by the human genome
Kinase inhibitors require
biomarkers to guide their application
Genomic DNA from lung cancer biopsies are tested via
PCR for a particular mutation of EGFR
if positive these patients will go on anti-EGFR therapies
Cell signaling is largely driven by
the transfer of phosphates
ATP is the major source of the phosphate group that is going to be transferred by a kinase to a target protein
What is a common target of several kinases
tyrosine
serine, threonine, and lipids can also be phosphorylated
things with an OH group can be phosphorylated
What balance the activity of kinases
phosphatases - by removing phosphates
Cell signaling
ligand binds to tyrosine kinase –> receptors dimerize –> activated –> phosphorylates
General structure of kinases
made up of N- and C-lobes connected by a hinge region
activation loop controls access to the active site
Types of kinase inhibitors
type I, II, and III
Type I inhibitors
bind to the active conformation of the kinase
Type II inhibitors
bind and stabilize the inactive conformation of the kinase
Type III inhibitors
occupy an allosteric pocket outside of the ATP-binding pocket
Competitive inhibitors
bind kinase in a reversible fashion and therfore must compete with ATP for binding
Covalent inhibitors
covalently bind with a reactive nucleophilic cysteine residue proximal to the ATP binding site, resulting in blockage of the ATP site and irreversible inhibition
EGFR targeted kinase inhibitors
gefitinib, afatinib, neratinib, dacomitinib, erlotinib, osimertinib, lapatinib, tucatinib
Patients with mutations in EGFR cause
the receptor to be constitutively activated
patients with these mutations show an enhanced response to EGFR inhibitors
Epidermal growth factor receptor (EGFR)
EGFR functions through tyrosine kinase activity; EGFR signaling induces cell proliferation
EGFR is a protein on cells that helps them grow; EGFR is overexpressed in human cancer
Gefitinib and erlotinib
erlotinib: small molecule reversible inhibitor of EGFR tyrosine kinase; competitively inhibits enzyme by binding to ATP binding site in kinase domain –> inhibition of kinase activity turns off signal to proliferate
approved for pts with metastatic NSCLC whose tumors have EGFR exon 19 or exon 21 mutations
Afatinib
covalent inhibitor of all ErbB receptors
approved for EGFR mutant NSCLC with EGFR mutations
dacomitinib same thing
What is the common SE of EGFR inhibitors
rash
if rash is present, more likely to respond well to inhibitor
What causes resistance to geftinib
T790M
What inhibitor works with the T790M mutation
osimertinib - covalent kinase inhibitor
bind in site with methionine, can inhibit mutant version
Lapatinib
small molecule tyrosine kinase inhibitor that blocks HER2 and EGFR signaling; EGFR forms a hetrodimer with HER2, HER2 is amplified in breast cancer
selective for HER2+ breast cancer
reversible inhibitor of EGFR and HER2
watch for sx of CHF
Tucatinib
small molecule tyrosine kinase inhibitor that preferentially binds HER2
selective for tx of HER2+ breast cancer
reduced AEs compared to others, no rash SE
FLT3 mutations in acute myeloid leukemia
FLT3 mutation increases dimerization of receptors
either an internal tandem duplication or activating mutation in tyrosine kinase domain
FLT3 ligand is a cytokine receptor important for hematopoietic cell survival + proliferation
mutations lead to increased proliferation and decreased apoptosis
FLT3 inhibitors
1st gen: midostaurin - broad kinase inhibitor (more toxic)
2nd gen: crenolanib - more specific
type II inhibitors: quizartinib - specific for ITD mutations
Chromosomal translocations
philadelphia chromosome (Ph1) is the prototype chromosomal translocation
formed by joining the 5’ portion of the Bcr gene with teh 3’ portion of the Abl gene –> Bcr-Abl –> transcribed into mRNA –> translated into unique protein not found in normal cells
Ph1 chromosome in 95% of chronic myeloid leukemia
Bcr-Abl drives
several proliferation pathways
acts as a kinase that is overexpressed to then drive cell proliferation
Imatinib
the Abl protein is a tyrosine kinase; the kinase activity of the Bcr-Abl chimeric protein is constitutively active, resulting in malignancy
imatinib is a type II small molecule inhibitor of the Abl tyrosine kinase –> results in reduced proliferation and enhanced apoptotic cell death in CML and GIST
indication for CML
resistnace is a battle because pts need to be on Abl inhibitors for life
Ponatinib
BCR-Abl inhibitor
effective against all major mutant forms of BCR-Abl
inhibits gatekeeper mutation T3151 that is resistant to all other BCR-Abl compounds
________ is a significant driver event in lung cancer
EML4-ALK translocation
EML4-ALK translocation
wild type ALK is a transmembrane receptor tyrosine kinase similar to EGFR
when ALK is inappropriately fused to ELM4, it becomes cytoplasmic and constitutively active –> proliferation, metastatis, anti-apoptosis
Alectinib
more specific inhibitor of ALK
inhibits tyrosine kinase ALK
requires companion diagnostic test for fusion gene
indicated for ALK-positive and NSCLC
Brigatinib
approved for NSCLC that have ALK mutations
BRAF mutations in melanoma
lead to increase in cell proliferation and survival
Dabrafenib
2nd gen BRAF-V600 inhibitor
used in combo with trametinib for treating BRAF V600E/K-mutant metastatic melanoma
colorectal cancer does not respond to this drug
also for NSCLC positive for BRAF-600 mutations
Trametinib
inhibits kinase activity of MEK1 and MEK2
allosteric inhibitor
not indicated for pts who have received prior BRAF inhibitor therapy
AE: rash
Bruton’s tyrosine kinase in B-cell malignancies
BTK is important for normal B cell activity and B cell tumor growth
Ibrutinib
covalent inhibitor of BTK
used in MCL and CLL
Acalabrutinib
2nd gen covalent BTK inhibitor
also targets Cys481
more potent and selective than ibrutinib
for B-cell lymphoma
Rapamycin analogues
rapamycin also known as sirolimus
inhibit function of mammalian target of rapamycin (mTOR); mTOR is a serine threonine kinase
inhibits immune response by blocking IL-2 signaling transduction
Everolimus
approved for renal carcinoma
only inhibits mTORC1 and not mTORC2 which can lead to feedback activation of Akt
involved more in metabolism and apoptosis
What is a major problem with kinase inhibitors
resistance
kinase inhibitors only keep everything in remission, once you stop them, it comes back
goals of these therapies is to decrease the use of toxic chemotherapies
Prognostic molecular pathology
how will patients respond
trying to find markers of response
