Part One: Introduction to Small Molecule Tyrosine Kinase Inhibitors

Neha Vapiwala, MD and Geoffrey Geiger, MD
The Abramson Cancer Center of the University of Pennsylvania
Last Modified: September 13, 2010

In the past several years, tyrosine kinase inhibitors have taken on an increasingly important role in the treatment of cancer. Tyrosine kinases function to transfer phosphate groups from a molecule known as ATP (adenosine triphosphate) to tyrosine groups. ATP is often called the "molecular unit of currency" of intracellular energy transfer and it functions to transport chemical energy within cells for metabolism.

There are many tyrosine kinase (TK) and TK-like genes throughout the genome, which assist with intracellular functions, such as cell division, death, maturation, and migration. In tumor cells, all of these reactions are critical for the tumor to survive and spread throughout the body. By blocking the receptor, the goal is to prevent the cascade of reactions critical for tumor cell function and to inhibit its growth or survival. Not surprisingly, the anticancer properties resulting from TK inhibition have become an important focus for drug development. There are various ways of accomplishing TK inhibition and in this first section, we will be looking at FDA approved small molecule tyrosine kinase inhibitors (TKIs), which are summarized in the table below.

Table 1. Summary of Food and Drug Administration (FDA)-Approved Tyrosine Kinase Inhibitors (TKIs)

Drug (Trade name)


FDA-Approved Indications

Toxicities, Side Effects and Precautions




Chronic myeloid leukemia, acute lymphocytic leukemia

Rash; diarrhea; pleural effusion; fluid retention; mucositis; myelosuppression; QT interval prolongation

CBC; EKG; LFTs; weight; signs and symptoms of fluid retention

Erlotinib (Tarceva)


Non-small cell lung cancer, pancreatic cancer

Acneiform rash; diarrhea; loss of appetite; nausea and vomiting; fatigue; conjunctivitis; elevated LFTs

LFTs; signs of inflammatory or infectious sequelae in patients with dermatologic toxicity



Non-small cell lung cancer

Acneiform rash; diarrhea; loss of appetite; interstitial lung disease (rare); elevated LFTs; patients cannot smoke while on treatment

LFTs; signs of inflammatory or infectious sequelae in patients with dermatologic toxicity




Acute lymphocytic leukemia, chronic myeloid leukemia, gastrointestinal stromal tumors, hypereosinophilic syndrome, systemic

Rash; weight gain; edema; pleural effusion; cardiac toxicity (depression of LVEF); nausea and vomiting; arthralgias and myalgias; myelosuppression

CBC; LFTs; weight; signs and symptoms of fluid retention



Breast cancer with HER2/neu overexpression

Cardiac toxicity (depression of LVEF; QT prolongation); acneiform rash; palmar-plantar erythrodysesthesia (hand-foot syndrome); diarrhea; nausea, vomiting and dyspepsia; elevated LFTs

LVEF; EKG; electrolyte levels; LFTs

Nilotinib (Tasigna)



Chronic phase or accelerated Ph- positive CML for patients resistant/intolerant of prior imatinib therapy

Rash; nauseas and vomiting; myelosuppression; QTc prolongation; sudden death; electrolyte abnormalities; hepatic dysfunction; avoid in patients with hypokalemia, hypomagnesemia, long QT syndrome

CBC; LFTs; Serum lipase; baseline and periodic EKGs



Renal cell cancer, hepatocellular carcinoma

Hypertension; alopecia; bleeding; rash; palmar-plantar erythrodysesthesia (hand-foot syndrome); hypophosphatemia; diarrhea; nausea and vomiting; elevated amylase and lipase levels; myelosuppression; wound-healing complications; need to discontinue treatment temporarily for surgical procedures

Blood pressure; dermatologic toxicity (see left); amylase, lipase, and phosphate levels; CBC



Renal cell cancer, gastrointestinal stromal tumor

Nausea and vomiting; yellow discoloration of skin; hypothyroidism; depression of LVEF; adrenal function abnormalities; diarrhea; myelosuppression; mucositis; elevated lipase and creatinine levels; elevated LFTs; increased uric acid levels

Adrenal function in patients with trauma or severe infection, or in those undergoing surgery; blood pressure; EKG; LVEF; CBC; electrolyte levels (magnesium and potassium); phosphate levels; signs and symptoms of pancreatitis; thyroid function tests

Note: All small molecule inhibitors are administered orally. Most small molecule inhibitors undergo cytochrome P450 metabolism and are therefore subject to multiple potential interactions (e.g., with anticonvulsants, azole antifungals, dexamethasone, isoniazid [Nydrazid], macrolide antibiotics, nefazodone [Serzone, brand no longer available in the United States], protease inhibitors, rifampin [Rifadin], St. John’s wort, verapamil [Calan], and warfarin [Coumadin]).

Abbreviations: FDA = U.S. Food and Drug Administration; CBC = complete blood count; BCR-ABL = breakpoint cluster region-Abelson; PDGFR = platelet-derived growth factor receptor; EKG = electrocardiography; EGFR = epidermal growth factor receptor; LVEF = left ventricular ejection fraction; LFTs = liver function tests; Ph = Philadelphia chromosome; DVT = deep venous thrombosis; VEGFR = vascular endothelial growth factor receptor.

The agents listed above are presented in alphabetical order and are the current FDA-approved small molecule TK inhibitors. In the following section, we will review these agents in greater detail.

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