Cell Signaling in cancer, targeting inhibition of kinase activity - Dr. Wendt Flashcards
How many human kinases are there?
518
How many genes encoding potential kinases have been identified?
900
What are kinases?
One of the largest classes of proteins encoded by the human genome
How many currently approved kinase inhibitors?
66
What was the first approved kinase inhibitor?
Imatinib
What do kinase inhibitors require to guide their application?
biomarkers
How are mutations identified for kinase inhibitors?
From tumor biopsy and data that is used as predictors of drug response
Describe diagnostic molecular pathology
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
How is cell signaling driven?
Driven by the transfer of phosphates. Adenosine triphosphate (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
What can also be phosphorylated?
serine and threonine and lipids
What balances the activity of kinases by removing phosphates?
phosphatases
Which are better understood? Kinases or phosphatases?
Kinases.
Kinases are prime targets for small molecule inhibitors
What does the general structure of a kinase entail?
Generally made up of N- and C- lobes connected by a hinge region. An activation loop containing a Asp-Phe-Gly (DFG) motif control access to the active site
How many types of kinase inhibitors are there?
3
Describe a type I kinase inhibitor
Type I inhibitors bind to the active conformation of the kinase with the aspartate residue (white backbone) of the DFG motif pointing into the ATP-binding pocket
Describe a type II kinase inhibitor
Type II inhibitors bind and stabilize the inactive conformation of the kinase with the flipped aspartate residue facing outward of the binding pocket
***Can also engage in an active conformation
Describe a type III kinase inhibitor
Type III inhibitors occupy an allosteric pocket outside of the ATP-binding pocket
Describe competitive inhibitors
bind kinase in a reversible fashion and therefore must compete with ATP for binding
Describe covalent inhibitors
tend to covalently bind with a reactive nucleophilic cysteine residue proximal to the ATP-binding site, resulting in the blockage of the ATP site and irreversible inhibition (often need to be much more specific)
3 potential amino acid targets of phosphorylation
- serine
- threonine
- tyrosine
EGFR is activated in _________ cancer
lung
Mutations in EGFR cause the receptor to be ___________ activated. Patients with these mutations show an ___________ response to EGFF inhibitors
constitutively; enhanced
Afatinib and neratinib are __________ inhibitors
covalent
Which EGFR inhibitor was pulled (2005) and then reapproved (2015) for use?
Gefitinib
Gefitinib brand
Iressa
Epidermal growth factor receptor (EGFR) functions through __________
tyrosine kinase activity
EGFR signaling induces ___ ______________
cell proliferation
In 25 - 50% of human cancers, EGFR is _______________
overexpressed and has higher signaling activity
EGFR overexpression correlates with ______ prognosis
poor
Erlotinib is a small molecule __________ inhibitor of the _______ tyrosine kinase. It _____________ inhibits the enzyme by binding to the ATP binding site in the _________ domain
reversible; EGFR; competitively; kinase
Inhibition of kinase activity turns _____ signal to proliferate
off
Gefitinib and Erlotinib are approved for treatment of patients with metastatic non-small cell lung cancer (NSCLC) who tumors have EGFR ________ or _________ mutations
exon 19; exon 21 (L858R)
Gefitinib and Erlotinib are well tolerated. Most adverse effects are…
…fatigue, rash, diarrhea
Afatinib brand
Gilotrif
Afatinib is replacing older compounds and is a ___________ inhibitor of all ErbB receptors
covalent
What is afatinib approved for?
EGFR mutant non-small cell lung cancer (NSCLC) with EGFR mutations
What is another covalent inhibitor approved for non-resistant EGFR mutant lung cancer?
Dacomitinib
SE associated with EGFR inhibitors. It can be a good thing
rash. Not sure why/how this happens, but it indicates the disease is more stable
What causes resistance to Geftinib?
T790
Osimertinib is essentially a new ____ to fit the change in _____ that occurs upon acquisition of the _____ mutation
key; “lock”; T790M
What are the two third generation EGFR inhibitors?
Gefitinib and Osimertinib
The Abl protein is a __________
tyrosine kinase
Imatinib brand
Gleevec
Gleevec is a type ___ small molecule inhibitor of the Abl tyrosine kinase
II
Constitutive activity results in ____________
malignancy
Inhibition of the Abl tyrosine kinase results in both reduced __________ and enhanced ___________ in ____ and ____
proliferation; apoptotic cell death; CML; GIST
Primary indication for Imatinib
Treatment of chronic myelocytic leukemia (CML)
Toxicities of Imatinib
- nausea and vomiting
- fluid retention and edema
- neutropenia and thrombocytopenia frequent but mild
Ponatinib is a _________ inhibitor
BCR-Abl
Ponatinib is effective against all the major forms of __________
BCR-Abl
Notably, ponatinib can __________ the “gatekeeper” mutation ________ that is resistant to all other BCR-Abl compounds. All these compounds bind BCR-Abl in the _________ confirmation
inhibit; T315I; “DFG out”
Acalabrutinib is a _______ generation ________ inhibitor that similarly targets _______. It is more potent and more __________ than 1st generation
second; covalent BTK; Cys481; selective
Acalabrutinib is indicated for…
…B-cell lymphoma (Mantle cell)
What is a significant driver event in lung cancer?
EML4-ALK
What are the three biggest distributions of driver mutations in lung cancer?
- Unknown (36.4%)
- KRAS (25%)
- EGFR (23%)
Wild type ALK is a _________ receptor tyrosine kinase similar to EGFR
transmembrane
When ALK becomes inappropriately fused to ELM4 (or other genes) it becomes ___________ and ________ active. It occurs in ___ of non-small cell lung cancers
cytoplasmic; constitutively; 6%
Alectinib brand
Alecensa
Alectinib is a _____ ________ inhibitor of ALK
more specific
Alectinib inhibits tyrosine kinase called ________________. It requires a companion ________ test for the fusion gene
anaplastic lymphoma kinase (ALK); diagnostic
When is Alectinib indicated for treatment?
Indicated for the treatment of patients with anaplastic lymphoma kinase (ALK)- positive, metastatic non-small cell lung cancer (NSCLC) who have progressed on or are intolerant to crizotinib. This indication is approved under accelerated approval based on tumor response rate and duration of response
_________ also recently approved NSCLC that have ALK mutations
Brigatinib
Dabrafenib brand
tafinlar
Dabrafenib is a second generation _________ inhibitor
BRAF-V600
Dabrafenib indication
for use in combination with trametinib for treatment of BRAF V600E/K-mutant metastatic melanoma. Activation of wild type BRAF remains a problem, combination with Trametinib seems to stem induction of squamous cell carcinomas. Also approved for the NSCLC patients that test positive for BRAF-600 mutations
Colorectal cancer commonly has ___ and _____ mutations but these tumors do not respond to __________
Ras; BRAF-V600; Dabrafenib
Trametinib brand
Mekinist
Trametinib inhibits the kinase activity of _____ and _____
MEK1; MEK2
Trametinib was recently approved to be used in combination with…
…Dabrafenib
What is the first approved type III allosteric inhibitor
Trametinib
What is Trametinib’s limitation of use
Its not indicated for the treatment of patients who have received prior BRAF inhibitor therapy
Most common adverse reactions for Trametinib
- rash
- diarrhea
- lymphedema
____ is a lipid kinase that leads to the downstream activation of __________. This pathway is critical for cancer cell survival. Toxicity is a major issue with several of these compounds.
Phosphoinositide 3-kinase (PI3K); protein kinase B (PKB/AKT)
What is the first example of an isospecific compound
Alpelisib
Alpelisib brand
Piqray
How many isoforms of PI3K
4
What is the isoform of PI3K that is mutually activated in breast cancer?
alpha isoform. This cuts down on the toxicity seen from other PI3K inhibitors
What drives the indication for Alpelisib
PIK3CA mutations
Name 4 rapalogs
- sirolimus
- temsirolimus
- everolimus
- deforolimus
What do rapamycin analogues do?
These compounds inhibit the function of mammalian target of Rapamycin (mTOR). Originally developed as an antifungal but failed in this capacity and was pursued as an anticancer agent
What is rapamycin also known as
sirolimus
mTOR is a ______-______ kinase
serine-threonine
rapamycin analogues inhibit the immune response by blocking ________
IL-2 signaling transduction
Everolimus brand
Afinitor
In addition to oncology, Everolimus is also used in ____________ due to its ____________
oncology; immunosupressive effects
Everolimus is currently approved for…
…treatment of advanced renal carcinoma, in patients who have failed sunitinib or sorafenib
Everolimus only inhibits ________ and not ________ which can lead to feedback activation of ______
mTORC1; mTORC2; Akt
_________ remains a major issue
resistance
One of the goals of these “targeted” therapies is to decrease the use of ______ ___________. Targeting of one aspect/pathway involved in cell growth is not likely to produce a ________ response. Improved diagnoses will drive a continuing diagnosis in cancer.
toxic chemotherapies; durable
