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Tyrosine Kinase Inhibitors

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Last Update: July 18, 2023.

Continuing Education Activity

Tyrosine kinase inhibitors (TKI) are a group of pharmacologic agents that disrupt the signal transduction pathways of protein kinases by several modes of inhibition. This activity will review the currently available drugs, their mechanism of action, routes of administration, indications, contraindications, and adverse effects.


  • Outline the different types of tyrosine kinase inhibitor (TKI) drugs and the currently available TKIs.
  • Describe the mechanism of action of tyrosine kinase inhibitors.
  • Summarize the indications and contraindications for each type of tyrosine kinase inhibitor.
  • Review the adverse effects and toxicity of tyrosine kinase inhibitors.
Access free multiple choice questions on this topic.


Mutations, dysregulation, and overexpression of protein kinases are involved in a multitude of disease processes. Around 1 in every 40 human genes codes for a protein kinase and nearly half of those genes map to either disease loci or cancer amplicons.[1] Interest in protein kinase inhibitors began with the FDA approval of the tyrosine kinase inhibitor (TKI) imatinib in 2001. Imatinib is an oral chemotherapy medication designed to target the BCR-Abl hybrid protein, a tyrosine kinase signaling protein produced in patients with Philadelphia-chromosome-positive chronic myelogenous leukemia. Since the introduction of Imatinib, the application of TKIs has been ever-expanding, particularly for cancer treatment, due to tyrosine kinases' critical roles in cellular signaling.[2][3]

Tyrosine kinase enzymes (TKs) can be categorized into receptor tyrosine kinases (RTKs), non-receptor tyrosine kinases (NRTKs), and a small group of dual-specificity kinases (DSK) which can phosphorylate serine, threonine, and tyrosine residues. RTKs are transmembrane receptor that includes vascular endothelial growth factor receptors (VEGFR), platelet-derived growth factor receptors (PDGFR), insulin receptor (InsR) family, and the ErbB receptor family, which includes epidermal growth factor receptors (EGFR) and the human epidermal growth factor receptor-2 (HER2). NRTKs are cytoplasmic proteins that consist of nine families, including Abl, Ack, Csk, Fak, Fes/Fer, Jak, Src, Syk/Zap70, and Tec, with the addition of Brl/Sik, Rak/Frk, Rlk/Txk, and Srm, which fall outside the nine defined families. The most notable example of DSKs is the mitogen-activated protein kinase kinases (MEKs), which are principally involved in the MAP pathways.[1][4][5]

As of now, there are over 50 FDA-approved TKIs. Comprehensive lists of FDA-approved TKIs with additional information are available at NIH PubChem and FDA.gov. Due to the broad reach of this topic and the rapid development of new drugs, this list is not fully comprehensive.



   TKI Target

Mechanism of Action

As a whole, tyrosine kinases phosphorylate specific amino acids on substrate enzymes, which subsequently alter signal transduction leading to downstream changes in cellular biology. The downstream signal transduction set off by TKs can modify cell growth, migration, differentiation, apoptosis, and death. Constitutive activation or inhibition, either by mutations or other means, can lead to dysregulated signal cascades, potentially resulting in malignancy and other pathologies.[4][40] Therefore, blocking these initial signals via TKIs can prevent the aberrant action of the mutated or dysfunctional TKs.

Despite the diverse primary amino acid sequences, human kinases share similar 3D structures, particularly when it comes to the ATP-binding pocket located in the catalytically active region. The starting amino acid sequence (ASP-Phe-Gly or DFG) of the flexible activation loop that controls access to the activation site is also typically conserved.[41]

Kinase inhibitors are either irreversible or reversible. The irreversible kinase inhibitors tend to covalently bind and block the ATP site resulting in irreversible inhibition. The reversible kinase inhibitors can further subdivide into four major subtypes based on the confirmation of the binding pocket as well as the DFG motif.[3][42]

Below are listed various binding modes of TKIs.[3]

  • Type I inhibitors: competitively bind to the ATP-binding site of active TKs. The arrangement of the DFG motif in type I inhibitors has the aspartate residue facing the catalytic site of the kinase.
  • Type II inhibitors: bind to inactive kinases, usually at the ATP-binding site. The DFG motif in type II inhibitors protrudes outward away from the ATP-binding site. Due to the outward rotation of the DFG motif, many type II inhibitors can also exploit regions adjacent to the ATP-binding site that would otherwise be inaccessible.
  • Type III inhibitors: do not interact with the ATP-binding pocket. Type III inhibitors exclusively bind to allosteric pockets adjacent to the ATP-binding region.
  • Type IV inhibitors: bind allosteric sites far removed from the ATP-binding pocket.
  • Type V inhibitors: refer to a proposed subset of kinase inhibitors that exhibit multiple binding modes.[43]


Nearly all TKIs are effective when taken orally. Therapeutic loading and maintenance dosages are unique to each drug and should require unique dosing for each patient. When administering specific TKIs, many factors can contribute to reduced potency and the development of acquired resistance. These factors include such as whether or not food intake affects bioavailability, the mechanism of drug metabolism and elimination, liver and kidney function, drug-drug interactions, the presence of other medications that alter stomach pH, and patient demographics.[44][45][46]

Adverse Effects

Adverse events of TKIs are usually dose-based, with broad side effect profiles unique to each drug. However, due to similarities in drug targets, different classes of TKIs can have similar side effect profiles. Clinicians use BCR-Abl and KIT inhibitors to treat Philadelphia chromosome-positive CML and GIST, respectively.[47] Both KIT and BCR-Abl inhibitors, Imatinib, in particular, are known to cause adverse cutaneous drug reactions.[48]

EGFRs are a large family of RTKs associated with several cancers, including NSCL, breast, colorectal, pancreatic, esophageal, and head-and-neck cancers. The most common severe adverse effects associated with EGRF inhibitors are related to cutaneous adverse drug reactions.[48][49] The reason for this association is likely due to EGFRs’ role in normal skin integrity. Inhibition of EGFR hinders integumental function leading to dysfunctional epidermal differentiation and re-epithelialization, resulting in skin erosions.[49]

Angiogenesis is a critical step in cancer growth. VEGF is a key inducer of pathological angiogenesis expressed in nearly all human tumors.[50] Due to VEGF’s role in blood vessel survival and plasticity, TKIs that inhibit VEGFR carry associations with several cardiovascular toxicities, particularly hypertension.[51][52] This toxicity is likely because VEGF is necessary for adequate nitric oxide production. Inhibition of VEGF, therefore, results in elevated systemic vascular resistance.[53][54] Because VEGF is vital to endothelial cell survival, anti-VEGF therapy can diminish the integrity and regenerative capacity of endothelial cells, causing pro-coagulant changes. The long-term weakening and diminished integrity of blood vessel walls can eventually lead to thrombosis and hemorrhage.[55] Other adverse events associated with VEGFR TKIs include: renal injury, left ventricular dysfunction, cerebral and intestinal hemorrhage, cardiac ischemia, thrombosis, and skin reactions.[38]

Common adverse events related to TKIs are listed below. Not all adverse events are associated with every TKI, occurring at different frequencies depending on the drug.


  • Fatigue
  • Fevers/Chills
  • Weight loss/gain


  • Abdominal pain
  • Diarrhea
  • Dysgeusia
  • Constipation
  • Nausea/vomiting
  • Hepatotoxicity
  • Stomatitis


  • Hypertension
  • Hypotension
  • Congestive heart failure
  • Thrombosis
  • Cardiac ischemia
  • Myocardial infarction
  • Strokes
  • Intestinal hemorrhage
  • QT interval prolongation


  • Steven Johnson syndrome
  • Toxic epidermal necrolysis
  • Drug rash with eosinophilia and systemic symptoms
  • Acute generalized exanthematous pustulosis
  • Palmar-plantar erythrodysesthesia
  • Maculopapular rashes
  • Cheilitis
  • Facial edema
  • Eczema
  • Pruritis
  • Photosensitivity
  • Xerosis
  • Alopecia
  • Hair color changes
  • Paronychia


  • Hypokalemia
  • Thyroid dysfunction
  • Lacrimation


  • Anemia
  • Thrombocytopenia
  • Neutropenia
  • Bruising


  • Myalgias
  • Arthralgia


  • Central serous retinopathy
  • Retinal pigment epithelial detachment
  • TKI keratitis


  • Kidney dysfunction
  • Proteinuria


  • Interstitial pulmonary disease
  • Pneumonia
  • Upper respiratory tract infection
  • Dyspnea
  • Epistaxis
  • Rhinorrhea


  • Cognitive impairment
  • Peripheral neuropathy
  • Headaches
  • Dizziness


There are very few contraindications for TKIs. Considering the use of TKIs in life-extending cancer therapy, the benefits associated with TKI use generally outweigh the risks.[56] Data concerning TKI use in pregnancy is sparse; however, with rising rates of advanced maternal-age pregnancies, cancers requiring TKI therapy during pregnancy have become more common.[57][58] While there are several reports of successfully administering TKIs, such as erlotinib, imatinib, and nilotinib, during pregnancy, multiple studies demonstrate adverse events and teratogenic effects related to TKI use during pregnancy.[36][59][60][61]

Data on TKI use during pregnancy is still lacking in most cases. As a result, TKIs are typically co-prescribed with an effective contraception method during therapy and several weeks after discontinuing the TKI. Other limitations to using TKIs include severe adverse reactions. Patients at particular risk for one of the known adverse effects of the TKIs about to be prescribed, such as hypertension, interstitial lung disease, and long-QT syndrome, should receive an alternative therapy if possible.


While TKIs relieve the disease burden of most cancer patients, acquired resistance through various mechanisms remains a bottleneck in cancer targeted therapy. Patients require monitoring for disease progression after the initial benefit, which could be a sign of acquired resistance.[46] Genetic testing to identify known resistance mutations can also help guide genotype-directed therapy.


TKIs are generally well-tolerated, especially when compared to non-targeted cancer therapy. However, only a few of these drugs are selective for only one target. Due to the ubiquitous physiological role protein kinases play in the body, toxicities affecting various organs can occur. Organs commonly affected include the heart, lungs, liver, gastrointestinal tract, kidneys, thyroid, blood, and skin.[62]

The toxicity and efficacy of TKIs are often closely linked; this allows on-target toxic effects to act as biomarkers of effective pharmacological inhibition for certain TKIs. For example, skin rashes can serve as a monitoring mechanism for the effects of some TKIs that target EGFR and hypertension and can generally help monitor the inhibition of VEGFR.[63][64][65] However, the combined detrimental effects of both on-target and off-target toxicities can diminish a patient’s quality of life and limit the dose intensity of their medication, leading to sub-therapeutic treatment.

The optimal TKI of choice and dose is a requirement to reduce toxicities and adverse events. While TIKs are mainly administered at a fixed dose, several factors must guide dosing when devising an optimal TKI regimen. These factors include drug-drug/drug-food interactions, genetic polymorphisms of ABC transporters, patient adherence, intestinal absorption, distribution, metabolism, and elimination.[66][67] The interplay of multiple processes regulating the pharmacokinetics and pharmacodynamics of TKIs merits consideration when administering a TKI to titrate the optimal dosage.[68]

Enhancing Healthcare Team Outcomes

The development of TKI represents one of the most significant medical breakthroughs of the 21st century; however, one of the drawbacks of this drug class, endemic to small molecule therapies for cancer treatment in general, is the financial burden to the patient.[1] Kinase inhibitor therapy ranges from $5000 to $10,000 per month or more in the United States.[68] The significant financial burden may contribute to non-compliance resulting in disease progression and treatment resistance.[69] Clinicians, pharmacists, and other healthcare professionals should be aware of these financial burdens and discuss them along with the other potential physical toxicities of these drugs with the patient.

Given the non-specific nature of this drug class, it is imperative that therapy is ordered and subsequently followed through the collaborative efforts of an interprofessional team. This interprofessional team includes clinicians (MDs, DOs, NPs, PAs), specialists, nursing staff, and pharmacists. Each team member needs to be knowledgeable about the indications, dosing, and potential adverse effects of these drugs so they can counsel the patient regarding expectations and monitoring for adverse events, which will allow any needed changes in therapy to be made promptly, thereby driving optimal patient therapeutic outcomes. [Level 5]

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Disclosure: Robert Thomson declares no relevant financial relationships with ineligible companies.

Disclosure: Majid Moshirfar declares no relevant financial relationships with ineligible companies.

Disclosure: Yasmyne Ronquillo declares no relevant financial relationships with ineligible companies.

Copyright © 2024, StatPearls Publishing LLC.

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