Tyrosine Kinase Inhibitors

Robert Thomson; Majid Moshirfar; Yasmyne Ronquillo

Tyrosine Kinase Inhibitors

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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.

Objectives:

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.

Indications

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	Indication
Deucravacitinib	TYK2	moderate-to-severe plaque psoriasis
Avapritinib	PDGFR	GIST (gastrointestinal stromal tumors) [6]
Capmatinib	c-MET	NSCLC (non-small cell lung cancer) [7]
Pemigatinib	FGFR	Cholangiocarcinoma with FGFR2 fusions or rearrangements [8]
Ripretinib	KIT/PDGFR	GIST [9]
Selpercatinib	RET	NSCLC and thyroid cancer [10]
Selumetinib	MEK1/2	Neurofibromatosis type 1 [11]
Tucatinib	Her2	HER2-positive breast cancer [12]
Entrectinib	TRKA/B/C, ROS1	ROS1-positive NSCLC, Solid tumors with NTRK fusion proteins [13]
Erdafitinib	FGFR	Urothelial bladder cancers [14]
Fedratinib	JAK2	Myelofibrosis [15]
Pexidartinib	CSF1R	Tenosynovial giant cell tumors [16]
Upadacitinib	PDGFR	GIST [17]
Zanubrutinib	BTK	Mantle cell lymphoma [18]
Baricitinib	JAK1/2	Rheumatoid arthritis [19]
Binimetinib	MEK1/2	Melanoma [20]
Dacomitinib	EGFR	EGFR-mutant NSCLC [21]
Fostamatinib	Syk	Chronic immune thrombocytopenia [22]
Gilteritinib	Flt	Acute myelogenous leukemia (AML) [23]
Larotrectinib	TRKA/B/C	Solid tumors with NTRK fusion proteins [24]
Lorlatinib	ALK	ALK-positive NSCLC [25]
Acalabrutinib	BTK	Mantle cell lymphoma, chronic lymphocytic leukemia (CLL), small lymphocytic lymphomas [26]
Brigatinib	ALK	ALK-positive NSCLC [21]
Midostaurin	Flt3	AML, advanced systemic mastocytosis, mast cell leukemia [27]
Neratinib	HER2	HER2-positive breast cancer [21]
Alectinib	ALK, RET	ALK-positive NSCLC [28]
Cobimetinib	MEK1/2	combination therapy with vemurafenib for BRAF-positive melanoma [29]
Lenvatinib	VEGFR, RET	Differentiated thyroid cancer [30]
Osimertinib	EGFR	NSCLC [31]
Ceritinib	ALK	ALK-positive NSCLC resistant to crizotinib [32]
Nintedanib	FGFR	Idiopathic pulmonary fibrosis [33]
Afatinib	EGFR, HER2, ErB4	NSCLC [31]
Ibrutinib	BTK	CLL, graft vs. host disease, mantle cell lymphoma, marginal zone lymphoma [26]
Trametinib	MEK1/2	Melanoma [34]
Axitinib	VEGFR	Advanced renal cell carcinoma [35]
Bosutinib	BCR-Abl	Chronic myelogenous leukemia (CML) [36]
Cabozantinib	RET, VEGFR	Advanced medullary thyroid cancer, hepatocellular and renal cell carcinoma [37]
Ponatinib	BCR-Abl	Philadelphia chromosome-positive CML or acute lymphoblastic leukemia (ALL) [36]
Regorafenib	VEGFR	Colorectal cancer and hepatocellular carcinoma, GIST [37]
Tofacitinib	JAK3	Rheumatoid arthritis [19]
Crizotinib	ALK, ROS1	ALK or ROS1-positive NSCLC [37]
Ruxolitinib	JAK1/2/3, Tyk	Myelofibrosis, polycythemia vera [37]
Vandetanib	VEGFR2	Medullary thyroid cancer [37]
Pazopanib	VEGFR	Renal cell carcinoma, soft tissue sarcomas [37]
Lapatinib	EGFR, HER2	HER2-positive breast cancer [21]
Nilotinib	BCR-Abl	Philadelphia chromosome-positive CML [36]
Dasatinib	BCR-Abl	CML [36]
Sunitinib	VEGFR2	GIST, pancreatic neuroendocrine tumors, renal cell carcinomas [38]
Sorafenib	VEGFR	Hepatocellular carcinoma, renal cell carcinoma, differentiated thyroid cancer [3]
Erlotinib	EGFR	NSCLC, pancreatic cancer [31]
Gefitinib	EGFR	NSCLC [31]
Imatinib	BCR-Abl, KIT, PGFR	Philadelphia chromosome-positive CML or ALL, aggressive systemic mastocytosis, chronic eosinophilic leukemia, hypereosinophilic syndrome, dermatofibrosarcoma protuberans, GIST, myelodysplastic/myeloproliferative disease [36][39]

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]

Administration

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.

General

Fatigue
Fevers/Chills
Weight loss/gain

Gastrointestinal

Abdominal pain
Diarrhea
Dysgeusia
Constipation
Nausea/vomiting
Hepatotoxicity
Stomatitis

Cardiovascular

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

Dermatological

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

Endocrine

Hypokalemia
Thyroid dysfunction
Lacrimation

Hematologic

Anemia
Thrombocytopenia
Neutropenia
Bruising

Musculoskeletal

Myalgias
Arthralgia

Ophthalmic

Central serous retinopathy
Retinal pigment epithelial detachment
TKI keratitis

Renal

Kidney dysfunction
Proteinuria

Respiratory

Interstitial pulmonary disease
Pneumonia
Upper respiratory tract infection
Dyspnea
Epistaxis
Rhinorrhea

Neurological

Cognitive impairment
Peripheral neuropathy
Headaches
Dizziness

Contraindications

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.

Monitoring

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.

Toxicity

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]

Details

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