Kinase inhibitors Flashcards
SIGNAL TRANSDUCTION THROUGH KINASES DRIVES PROLIFERATION
Normal Mechanism of EGFR and HER2
Growth factors bind to EGFR on the membrane
HER2 do not have a ligand for binding
HER2 is amplified in breast cancers: at high concentrations, forms heterodimers that signal transduction without ligand binding
How do kinases work?
Ligand binds to the extracellular binding domain–> receptor dimerizes–> activates kinase–> kinases phosphorylate proteins/ligands by binding to ATP
ATP is a major source of the phosphate group that is going to be transferred by a kinase to a target protein (phosphorylation)
Phosphatases balance the activity of kinases removing phosphates
Common targets of kinase phosphorylation: tyrosine, serine, threonine, glutamate
2 causes of cancer related to kinases/phosphatases: activation of kinases, deletion of phosphatases
How to choose a kinase inhibitor?
-Diagnostic Molecular Pathology:
Mutations can be identified by a tumor biopsy and serve as biomarkers guide selection of kinase inhibitor therapies–> driven by genomic data
Ex: genomic DNA from a lung cancer biopsy are tested via PCR for a mutation of EGFR–> if EGFR +–> EGFR inhibitor
-Prognostic molecular pathology:
Sampling large samples of patients and try to identify why some patients do well and other patients do not on certain targeted therapies
Oncotype Dx: helps predict the recurrence and can prevent overtreatment but they DO NOT drive indications for specific therapies
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
Reversible inhibitors (competitive)–> competes with ATP for binding
Type 1: bind to the active conformation
Type 2: bind and stabilizes the inactive conformation
Type 3: bind an allosteric pocket outside of the ATP binding pocket
Irreversible inhibitors (covalent)–> covalently binds to cysteine residue proximal to ATP binding site
fms-like tyrosine kinase 3
Found in 30% of acute myeloid leukemia
Normal: FLT3 ligand is a cytokine receptor important for hematopoietic cell survival and proliferation
Types of FLT3 mutations:
Internal tandem duplication: increases dimerization of kinase
Activating mutation in tyrosine kinase domain
Types of FLT3 inhibitors:
1st gen: broad kinase inhibitors
2nd gen: more specific
Type 2: specific for ITD mutations
Gefitinib, Erlotinib
MOA: type 1 reversible inhibitor of EGFR tyrosine kinase
Competitivity inhibits the enzyme by binding to the ATP binding site in the kinase domain–>stops cell proliferation
Indication: treatment of patients with metastatic NSCLC with EGFR exon 19 and 21 mutations
SE: diarrhea, rash, fatigue
Pearl: T790M mutation causes resistance to Gefitinib
Afatinib
2nd generation
covalent inhibitor of all ErbB receptors
Indication: treatment of patients with metastatic NSCLC with EGFR exon 19 and 21 mutations
SE: diarrhea, rash, fatigue
Pearl: T790M mutation causes resistance to Gefitinib
Osimertibib
3rd generation
covalent inhibitor of EGFR tyrosine kinase with T790M mutant
Indication: treatment of patients with metastatic NSCLC with EGFR exon 19 and 21 mutations
treatment of patients with metastatic EGFR T790M mutation NSCLC
Lapatinib
reversible tyrosine kinase inhibitor of both EGFR and HER2
treatment of HER2+ advanced metastatic breast cancer in patients who have progressed (combination with capecitabine)
SE: diarrhea, N/V, symptoms with congestive heart failure
Tucatinib
Reversible inhibitor with preference of HER2
Indication: 2nd line therapy for treatment of HER2+ advanced metastatic breast cancer in patients who have progressed (combination with capecitabine and trastuzumab)
SE: much less compared to Lapatinib
Midostaurin
1st gen FLT3 inhibitor
Tx of acute myeloid leukemia
Crenolanib
2nd gen FLT3 inhibitor
tx of acute myeloid leukemia
Quizartinib
Type 2 FLT3 inhibitor specific for ITD mutations
Bcr-Abl (philadelphia chromosome)
Formed by joining the 5’ portion of the Bcr gene (chromosome 22) with the 3’ portion of the Able gene (chromosome 9)–> chimeric Bcr-Abl is transcribed into mRNA–> RNA is translated into a protein not found in normal cells–> proliferation and constitutively active
Responsible for approx. 95% of chronic myeloid leukemia
EML4-ALK
ALK is normally a transmembrane receptor tyrosine kinase
When ALK becomes inappropriately fused to ELM4, it becomes cytoplasmic and constitutively active
Responsible for approx…6% of NSCLC
BRAF mutations
Mutation of BRAF^V600 activates downstream MEK and ERK pathways to increase cell proliferation and survival
Responsible for melanoma cancers
Bruton’s Tyrosine Kinase (BTK)
BTK is important in normal B cell activity and B cell tumor growth
Responsible for mantle cell lymphoma and chronic lymphocytic leukemia
mTOR
Serine-threonine kinase
Imatinib
intracellular tyrosine kinase inhibitor
type 2 inhibitor of Abl tyrosine kinase
inhibition of the Abl tyrosine kinase results in reduced proliferation and enhanced apoptotic cell death
indication: treatment of chronic myeloid leukemia
SE: N/V, edema, neutropenia, and thrombocytopenia
pearls: resistance is a battle as patients are on this for life
Ponatinib
inhibitor of Abl tyrosine kinase + all mutant forms
can inhibit the “gatekeeper” mutation T315I
chronic myeloid leukemia
Alectinib and Brigatinib
inhibitor of ALK (anaplastic lymphoma kinase)
treatment of patients with ALK+, metastatic NSCLC who have progressed on crizotinib
requires a companion diagnostic test for the fusion gene
Dabrafenib
2nd generation
MOA: BRAF^V600 inhibitor
Treatment of BRAF v600E/K-mutant metastatic melanoma
Treatment of BRAF-V600 mutant NSCLC
DOES NOT TREAT COLORECTAL CANCER MUTATIONS
Trametinib
type 3 allosteric inhibitor of MEK1 and MEK2
SE: diarrhea, rash, lymphedema
TRAMETINIB IS NOT INDICATED FOR PATIENTS WHO HAVE HAD PREVIOUS BRAF INHIBITORS
Acalabrutibib
2nd generation
covalent BTK inhibitor and Cys481
treatment for patients with B-cell lymphoma
Everolimus
rapamycin analog
inhibits mTORC1 but not mTORC2
can lead to feedback activation of Akt
treatment in advanced renal carcinoma in patients who have failed sunitinib or sorafenib
