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TYROSINE KINASE INHIBITORS

Ahmad Aljifri

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Outline

• Introduction-Protein Kinase-Categories of Protein Kinases-Tyrosine Kinase-Tyrosine Kinase Types-Targeted Therapy

• Tyrosine Kinase Inhibitor

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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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Categories of Protein Kinases

1. Kinases that specifically phosphorylate tyrosine residues.

2. Kinases that phosphorylate serine and threonine residues.

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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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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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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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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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Tyrosine Kinase Inhibitor

1. BCR-ABL Tyrosine Kinase Inhibitors eg: Imatinib, Dasatinib, Nilotinib.

2. Epidermal Growth Factor ReceptorTyrosine Kinase Inhibitors eg: Gefitinib, Lapatinib.

3. Vascular Endothelial Growth Factor Tyrosine Kinase Inhibitors eg: Semaxinib, Vandalinib, Sunitinib, Sorafenib.

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Imatinib (Gleevec)

• MOA:Inhibits Bcr-Abl tyrosine kinase, the constitutive abnormal gene product of the Philadelphia chromosome in chronic myeloid leukemia (CML).

• Indication:Ph+ CMLPh+ ALLGIST

website:http://www.gleevec.com/index.jsp

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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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Dasatinib

• MOA:BCR-ABL tyrosine kinase inhibitor; targets most imatinib-resistant BCR-ABL mutations.

• Indication:Ph+ CMLPh+ ALL

website:https://www.sprycel.com/index.aspx

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DasatinibToxicity:• 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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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

• websitehttp://www.iressa.com

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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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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.

websitehttp://www.tykerb.com/

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LapatinibToxicity• 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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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)

websitehttp://www.nexavar-us.com/scripts/pages/en/patient/index.php

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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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Drug Interactions

Strong CYP3A4 Inhibitors:ketoconazole, itraconazole, voriconazole, posiconazoleclarithromycin, telithromycinatazanavir, indinavir, nelfinavir, ritonavir, saquinavir, nefazodone

Moderate CYP3A4 Inhibitors:fluconazole, erythromycin, aprepitant, grapefruit juice,verapamil, cimetidine

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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