TKI introduction and some of its drugs and side effects many thanks to Vijay Yerroju most of the info is taken from his presentation on TKI

1. TYROSINE KINASE
INHIBITORS
Ahmad Aljifri
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2. Outline
• Introduction
-Protein Kinase
-Categories of Protein Kinases
-Tyrosine Kinase
-Tyrosine Kinase Types
-Targeted Therapy
• Tyrosine Kinase Inhibitor
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3. Protein Kinase
• Is kinase enzyme that modifies other proteins by chemically
adding phosphate groups to them (phosphorylation)
• The phosphate is often taken from ATP
• Phosphorylation of proteins by kinases is an
important mechanism in communicating
signals within a cell (signal transduction)
and regulating cellular activity, such as
cell division.
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4. Categories of Protein Kinases
1. Kinases that specifically phosphorylate
tyrosine residues.
2. Kinases that phosphorylate serine and
threonine residues.
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5. Tyrosine Kinase
• Is an enzyme that can transfer a phosphate group
from ATP to a protein in a cell.
• It functions as an "on" or "off" switch
in many cellular functions.
• The phosphate group is attached to the
amino acid tyrosine on the protein.
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6. Tyrosine Kinase Types
1. Receptor tyrosine kinases
eg: EGFR, PDGFR, FGFR
2. Non-receptor tyrosine kinases
eg: SRC, ABL, FAK and Janus kinase
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7. 7

8. 8

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10. Oncogenic Activation of Receptor Tyrosine Kinases
• Normally the level of cellular tyrosine kinase
phosphorylation is tightly controlled by the
antagonizing effect of tyrosine kinase
and tyrosine phosphatases.
• Some Common mechanisms
of oncogenic activation:
1. Activation by mutation
2. BCR-ABL and human leukemia
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11. Targeted Therapy
• is a type of medication that blocks the growth of cancer
cells by interfering with specific targeted molecules needed
for carcinogenesis and tumor growth.
• rather than by simply interfering with all rapidly dividing
cells (e.g. with traditional chemotherapy).
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13. Tyrosine Kinase Inhibitor
1. BCR-ABL Tyrosine Kinase Inhibitors
eg: Imatinib, Dasatinib, Nilotinib.
2. Epidermal Growth Factor Receptor
Tyrosine Kinase Inhibitors
eg: Gefitinib, Lapatinib.
3. Vascular Endothelial Growth
Factor Tyrosine Kinase Inhibitors
eg: Semaxinib, Vandalinib,
Sunitinib, Sorafenib.
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14. Imatinib (Gleevec)
• MOA:
Inhibits Bcr-Abl tyrosine kinase, the constitutive abnormal
gene product of the Philadelphia chromosome in chronic
myeloid leukemia (CML).
• Indication:
Ph+ CML
Ph+ ALL
GIST
website:
http://www.gleevec.com/index.jsp
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15. Imatinib (Gleevec)
Toxicity:
• Cardiovascular: Edema/fluid retention (11% to 86%)
• Central nervous system: Fatigue (29% to 75%), pain (≤47%), fever (6% to 41%),
headache (8% to 37%), dizziness (5% to 19%)
• Dermatologic: Rash (9% to 50%), dermatitis (GIST ≤39%), alopecia (GIST 10% to
15%)
• Endocrine & metabolic: LDH increased (GIST ≤60%),
• Gastrointestinal: Nausea (42% to 73%; Ph+ ALL), diarrhea (25% to 59%; Ph+
ALL), vomiting (11% to 58%), abdominal pain (3% to 57%), anorexia (≤36%),
weight gain (5% to 32%),
• Hematologic: Anemia (25% to 80%), leukopenia (GIST 5% to 47%), hemorrhage
(3% to 53%), neutropenia (12% to 16%)
• Hepatic: Transaminases and/or bilirubin increased (57%)
• Neuromuscular & skeletal: Muscle cramps (16% to 62%)
• Ocular: Periorbital edema (29% to ≤74%)
• Renal: Serum creatinine increased (≤44%)
• Respiratory: cough (11% to 27%), upper respiratory tract infection (3% to 21%)
• Miscellaneous: Infection (Ph+ ALL 53%; GIST ≤28%)
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16. Dasatinib
• MOA:
BCR-ABL tyrosine kinase inhibitor; targets most imatinib-
resistant BCR-ABL mutations.
• Indication:
Ph+ CML
Ph+ ALL
website:
https://www.sprycel.com/index.aspx
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17. Dasatinib
Toxicity:
• Cardiovascular: Fluid retention (21% to 35%)
• Central nervous system: Headache (12% to 33%), fatigue (8% to
24%), fever (5% to 18%)
• Dermatologic: Rash (11% to 21)
• Endocrine & metabolic: Hypophosphatemia (5% to 18%)
• Gastrointestinal: Diarrhea (18% to 31%), nausea (9% to 24%),
vomiting (5% to 16%), abdominal pain (3% to 12%)
• Hematologic: Thrombocytopenia (19% to 85%), neutropenia (22%
to 79%), anemia (11% to 74%), neutropenic fever (1% to 12%)
• Neuromuscular & skeletal: Musculoskeletal pain (≤19%)
• Respiratory: Pleural effusion (12% to 24%)
• Miscellaneous: Infection (9% to 12%)
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18. Gefitinib
• MOA:
Gefitinib is a tyrosine kinase inhibitor (TKI) which inhibits
numerous tyrosine kinases associated with transmembrane cell
surface receptors found on both normal and cancer cells, including
the tyrosine kinase associated with the epidermal growth factor
receptor, EGFR.
• Indications:
Non-small Cell Lung Cancer (NSCLC)
Monotherapy for continued treatment of locally advanced or
metastatic NSCLC after failure of both platinum-based and
Docetaxel regimens
• website
http://www.iressa.com
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19. Gefitinib
Toxicity
• Dermatologic: Rash (43% to 54%), acne (25% to 33%), dry
skin (13% to 26%), paronychia (14%)
• Gastrointestinal: Diarrhea (48% to 67%), nausea (13% to
18%), vomiting (9% to 12%)
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20. Lapatinib
• MOA:
Tyrosine kinase (dual kinase) inhibitor; inhibits EGFR (ErbB1) and
HER2 (ErbB2). Combination therapy with lapatinib and endocrine
therapy may overcome endocrine resistance occurring in HER2+
and hormone receptor positive disease.
• Indications:
Metastatic Breast Cancer in combination with Capecitabine in
patients whose tumors overexpress HER2 and who have received
prior therapy including an Anthracycline, a Taxane, and
Trastuzumab.
website
http://www.tykerb.com/
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21. Lapatinib
Toxicity
• Central nervous system: Fatigue (10% to 20%), headache (≤14%)
• Dermatologic: (hand-and-foot syndrome) (with capecitabine: 53%),
rash (28% to 44%), alopecia (≤13%)
• Gastrointestinal: Diarrhea (64% to 65%), nausea (31% to 44%),
vomiting (17% to 26%),
• Hematologic: Anemia (with capecitabine: 56%), neutropenia (with
capecitabine: 22%)
• Hepatic: total bilirubin increased (22% to 45%)
• Neuromuscular & skeletal: weakness (≤12%), back pain (≤11%)
• Respiratory:Dyspnea (≤12%)
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22. Sorafinib
• MOA:
Multikinase inhibitor; inhibits tumor growth and angiogenesis by
inhibiting intracellular Raf kinases, and cell surface kinase receptors
(VEGFR-1, VEGFR-2, VEGFR-3, PDGFR-beta, cKIT, FLT-3, and
RET).
• Indications:
Treatment of advanced renal cell cancer (RCC); treatment of
unresectable hepatocellular cancer (HCC)
website
http://www.nexavar-us.com/scripts/pages/en/patient/index.php
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23. Sorafinib
Toxicity
• Cardiovascular: Hypertension (9% to 17%)
• Central nervous system: Fatigue (37% to 46%),
• Dermatologic: Rash (19% to 40%), hand-foot syndrome (21% to
30%), alopecia (14% to 27%)
• Endocrine & metabolic: Hypoalbuminemia (≤59%),
• Gastrointestinal: Diarrhea (43% to 55%), weight loss (10% to
30%),, nausea (23% to 24%), vomiting (15% to 16%), constipation
(14% to 15%)
• Hematologic: Lymphopenia (23% to 47%),
• Hepatic: Liver dysfunction (≤11%)
• Neuromuscular & skeletal: Muscle pain, weakness
• Respiratory: Dyspnea (≤14%), cough (≤13%)
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24. Drug Interactions
Strong CYP3A4 Inhibitors:
ketoconazole, itraconazole, voriconazole, posiconazole
clarithromycin, telithromycin
atazanavir, indinavir, nelfinavir, ritonavir, saquinavir,
nefazodone
Moderate CYP3A4 Inhibitors:
fluconazole, erythromycin, aprepitant, grapefruit juice,
verapamil, cimetidine
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25. Reference
• Managing Side Effects of TKI Therapy to Optimize Adherence in Patients with
Chronic Myeloid Leukemia http://goo.gl/CE49F
• http://www.cancer.gov/aboutnci/ncicancerbulletin/archive/2005/030805
• http://www.Lexicopm.com
• https://www.youtube.com/watch?v=zE4BkAw_lL4
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