Background   ‘Targeted cancer therapy’ is an umbrella term for a diverse group of antineoplastic agents developed to block the growth and progression of malignant cells by interfering with intracellular pathways responsible for tumor growth (1). Their use in treating cancer is expanding, including for patients with far-advanced disease who may not otherwise have been eligible for traditional cytotoxic chemotherapies (2). This Fast Fact reviews types of targeted cancer therapies and side effects seen with tyrosine kinase inhibitors (TKIs). Part 2 addresses monoclonal antibody targeted agents.

Pharmacology   While conventional cytotoxic chemotherapies generally interfere non-selectively with the proliferation of all rapidly dividing cells in the body, targeted agents are meant to block one or more molecules essential for the proliferation of cancer cells. They can be categorized into two main groups.  

• Small molecule drugs are primarily TKIs. These are orally administered drugs with potential to inhibit various tyrosine kinases (TKs), intracellular enzymes that are mutated or over-expressed in malignant cells (3). TKIs competitively inhibit adenosine triphosphate at the catalytic binding site of the enzymes, compete with the substrate of TKs, or bind at alternative sites and induce a conformational change resulting in inhibition of the enzyme activity. Examples include imatinib (used to treat GIST tumors), sorafenib (hepatocellular cancer and renal cell cancer), inpatinib (Her-2 breast cancer), erlotinib (nonsmall cell lung cancer) dasatinib (CML).  Of note, generic names for TKIs usually end in “-ib.”  Side-effect profiles of the TKIs depend on the roles the individual enzymes play in intracellular signaling and overall cell function.
  • On-target toxicities such as hypertension, hypothyroidism, proteinuria, or hand-foot syndrome are related to the primary pharmacological effects of the drugs and occur when TKIs inhibit molecules/pathways required for normal cell function on intended targets in normal and cancer cells. They can sometimes be a biomarker for TKI efficacy.
  • Off-target toxicities such as fatigue, nausea, diarrhea, liver disease, and blood disorders are due to secondary pharmacological effects of the drugs and occur when molecules/pathways are inhibited that are not intended to be targeted by the TKI (4). They tend to be less predictable.
• Monoclonal antibodies (mAbs) are larger than TKIs and unable to enter cells. They are designed to bind selectively to specific tumor-associated antigens on the surface of cancer cells. MAbs are administered intravenously and can be used either in an unconjugated form or conjugated via a linker to cytotoxic molecules to help enhance their tumor selectivity and their anti-cancer effect (5). MAbs are more specific than TKIs, but due to their complex development process, more expensive than TKIs. See Fast Fact #277 for more information on mAbs. Of note, generic names usually end in “-ab.”

Common side effects of TKIs All TKIs can cause cytopenias and gastrointestinal side effects such as nausea/vomiting (3). Some TKIs cause headaches, muscle cramps, periorbital edema, and induce/ worsen symptoms of depression. Since TKIs are teratogenic, female patients of reproductive age should take appropriate measures to prevent pregnancy and/or stop breast-feeding during therapy. Although patients may be evaluated for specific risks prior to therapy (e.g. premorbid cardiovascular disease) no guidelines exist for prophylaxis against TKI toxicities. Side effects should be managed with general symptom management principles (6). Two main classes of side effects are discussed below.

Cardiovascular toxicities:  

• Mild to moderate hypertension requires only observation. For severe hypertension, there are no specific antihypertensive drugs which are recommended, except that nondihydropyridine calcium channel blockers (e.g. verapamil, diltiazem), which inhibit CYP3A4, should be avoided in conjunction with sunitinib and pazopanib (7).
• Left ventricular dysfunction manifestations range from asymptomatic EKG findings to severe heart failure. Predisposing factors include prior anthracycline therapy and TKI-induced hypertension (8).
• Pulmonary arterial hypertension (e.g. from dasatinib) is generally reversible with discontinuation (8).
• QTc interval prolongation occurs variably; whether this complication is class-wide is unknown. Although specific guidelines are lacking, caution is advised in patients with underlying cardiac disease and when other QTc prolonging drugs (such as many commonly used anti-emetics) are administered (8). Obtaining a baseline EKG is common, although empiric, practice.

Dermatologic toxicities:  

• A variety of nonspecific skin toxicities may occur with TKIs, including dry skin, hair color changes, skin discoloration, acral erythema, subungual hemorrhages, an acneiform rash, and hand-food syndrome, beginning several weeks after therapy initiation.
• Prior to initiating therapy, patients are advised to use sunscreens, enhance skin moisturizing, and avoid tight fitting shoes (9).
• No specific management guidelines exist for the acneiform rash; expert opinion recommends topical antibiotics (e.g. clindamycin 1% +/- benzoyl peroxide) or oral antibiotics (e.g. tetracycline, minocycline) and continuation of TKI therapy (9).
• Hand-foot syndrome (HFS, or palmar-plantar erythrodysesthesia, see Fast Fact #520) often arises within the first 6 weeks of therapy, worsens with continued chemotherapy (10). HFS usually resolves within 2-4 weeks of drug therapy interruption, and usually recurs if TKI is introduced at the same dose. Expert opinion suggests National Cancer Institute Grade 1 HFS (erythema without pain) be treated with keratolytics and emollients; Grade 2 HFS (skin changes and/or pain) requires topical corticosteroids and topical or systemic analgesics (including opioids); Grade 3 (ulcerative dermatitis and/or pain impeding function) requires TKI interruption and dose reduction. Other supportive therapies in use – all empiric – include pyridoxine, COX-2 inhibitors, gabapentinoids, systemic corticosteroids, regional cooling, and transdermal nicotine (10).

References 

1. Krause DS and Van Etten RA. Tyrosine kinases as targets for cancer therapy. N Engl J Med 2005; 353:172-87.
2. Amir E, Seruga B, Martinez-Lopez J, et al. Oncogenic targets, magnitude of benefit, and market pricing of antineoplastic drugs. J Clin Oncol 2011; 29:2543-9.
3. Hartmann JT, Haap M, Kopp HG, Lipp HP. Tyrosine kinase inhibitors – a review on pharmacology, metabolism and side effects. Curr Drug Metab 2009;10:470-81.
4. Shah DR, Shah RR and Morganroth J. Tyrosine kinase inhibitors: Their on-target toxicities as potential indicators of efficacy. Drug Saf 2013; 36:413-26. PMID:23620170.
5. Chari RVJ. Targeted Cancer Therapy: Conferring specificity to cytotoxic drugs. Acc Chem Res 2008; 41:98-107.
6. Mendez-Vidal MJ, Ortega EM, Pino AM, Valderrama BP, Vician R. Management of adverse events of targeted therapies in normal and special patients with metastatic renal cell carcinoma. Cancer Metastasis Rev 2012; 31(Suppl 1):S19–S27.
7. Micromedex® Healthcare Series [Internet database]. Greenwood Village, Colo: Thomson Reuters (Healthcare) Inc. Updated periodically.
8. Shah RR, Morganroth J, Shah DR. Cardiovascular safety of tyrosine kinase inhibitors: with a special focus on cardiac repolarisation (QT Interval). Drug Saf. 2013; 36:295–316.
9. Huang X, Patel S, Ahmed N, Seiter K, Liu D. Severe toxicity of skin rash, fever and diarrhea associated with imatinib: case report and review of skin toxicities associated with tyrosine kinase inhibitors. Drug Des Devel Ther. 2009; 2:215-9.
10. Lipworth AD, Robert C, Zhu AX. Hand-foot syndrome (hand-foot skin reaction, palmar-plantar erythrodysesthesia): focus on sorafenib and sunitinib. Oncology. 2009;77(5):257-71. doi: 10.1159/000258880.

Authors’ Affiliations:  National Institutes of Health Clinical Center, Bethesda, MD.
Conflicts of Interest Disclosure: The authors have not disclosed any relevant conflicts of interest.
Version History: First electronically published in December 2013; re-copy-edited in November 2015; reviewed and updated in September 2025.