The widespread prevalence and increasing incidence of cancer has imposed the introduction of new therapeutic approaches and medications. The elucidation of the key role of receptor tyrosine kinases (RTKs) in intercellular signaling and their involvement in fundamental processes, replication, growth, differentiation, and apoptosis, has provided substantial evidence linking their altered functionality to tumorigenesis.
This review aims to briefly discuss the role of RTKs in tumorigenesis and characterize tyrosine kinase inhibitors (TKIs), focusing on their mechanisms of action, pharmacodynamics, and pharmacokinetics as essential drugs in modern targeted cancer therapy.
Two primary mechanisms inhibit mutated or overexpressed RTKs. The first involves monoclonal antibodies targeting the extracellular domains of RTKs or their ligands, inhibiting RTK dimerization and activation, thus forming the group of extracellular TKIs. The second mechanism involves small-molecule TKIs targeting the intracellular tyrosine kinase domain of the receptors or other intracellular tyrosine kinases mediating their signaling pathways. Numerous mono- and multi-targeted TKIs have been developed, addressing one or more signaling pathways. Identifying specific mutations in individual patients and applying specific TKIs have introduced the principles of personalized cancer therapy. Most TKIs are well-tolerated and significantly improve patient survival. The selectivity of TKIs toward their targets determines their efficacy and safety profile.
Despite their advantages, TKI therapy is associated with significant toxic effects and high variability due to their pharmacokinetic features. Literature discusses the potential of therapeutic drug monitoring to optimize dosing, thereby enhancing efficacy and minimizing adverse side effects.
In summary, TKIs are pivotal medications in modern oncology that have revolutionized the treatment paradigm for numerous cancers.
Bray F, Laversanne M, Sung H, Ferlay J, Siegel RL, Soerjomataram I, et al. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2024;74(3):229–63. doi: 10.3322/caac.21834.
Esteban-Villarrubia J, Soto-Castillo JJ, Pozas J, San Román-Gil M, Orejana-Martín I, Torres-Jiménez J, et al. Tyrosine Kinase Receptors in Oncology. Int J Mol Sci. 2020 Nov 12;21(22):8529. doi: 10.3390/ijms21228529.
Broekman F. Tyrosine kinase inhibitors: Multi-targeted or single-targeted? World J Clin Oncol. 2011;2(2):80. doi: 10.5306/wjco.v2.i2.80.
Du Z, Lovly CM. Mechanisms of receptor tyrosine kinase activation in cancer. Mol Cancer. 2018 Dec;17(1):58. doi: 10.1186/s12943-018-0782-4.
Ebrahimi N, Fardi E, Ghaderi H, Palizdar S, Khorram R, Vafadar R, et al. Receptor tyrosine kinase inhibitors in cancer. Cell Mol Life Sci CMLS. 2023 Mar 22;80(4):104. doi: 10.1007/s00018-023-04729-4.
Wilkes GM. Targeted Therapy: Attacking Cancer with Molecular and Immunological Targeted Agents. Asia-Pac J Oncol Nurs. 2018;5(2):137–55. doi: 10.4103/apjon.apjon_79_17.
Dempsey N, Sandoval A, Mahtani R. Metastatic HER2-Positive Breast Cancer: Is There an Optimal Sequence of Therapy? Curr Treat Options Oncol. 2023 Sep;24(9):1120–37. doi: 10.1007/s11864-023-01108-w.
Keating GM. Pertuzumab: in the first-line treatment of HER2-positive metastatic breast cancer. Drugs. 2012 Feb 12;72(3):353–60. doi: 10.2165/11209000-000000000-00000.
Garcia J, Hurwitz HI, Sandler AB, Miles D, Coleman RL, Deurloo R, et al. Bevacizumab (Avastin®) in cancer treatment: A review of 15 years of clinical experience and future outlook. Cancer Treat Rev. 2020 Jun;86:102017. doi: 10.1016/j.ctrv.2020.102017.
Sakata S, Larson DW. Targeted Therapy for Colorectal Cancer. Surg Oncol Clin N Am. 2022 Apr;31(2):255–64. doi: 10.1016/j.soc.2021.11.006.
Koopman LA, Terp MG, Zom GG, Janmaat ML, Jacobsen K, Gresnigt-van den Heuvel E, et al. Enapotamab vedotin, an AXL-specific antibody-drug conjugate, shows preclinical antitumor activity in non-small cell lung cancer. JCI Insight. 2019 Nov 1;4(21):e128199, 128199. doi: 10.1172/jci.insight.128199.
Aprile G, Bonotto M, Ongaro E, Pozzo C, Giuliani F. Critical appraisal of ramucirumab (IMC-1121B) for cancer treatment: from benchside to clinical use. Drugs. 2013 Dec;73(18):2003–15. doi: 10.1007/s40265-013-0154-8.
Chan MM, Sjoquist KM, Zalcberg JR. Clinical utility of ramucirumab in advanced gastric cancer. Biol Targets Ther. 2015;9:93–105. doi: 10.2147/BTT.S62777.
Cameron F, Sanford M. Ibrutinib: first global approval. Drugs. 2014 Feb;74(2):263–71. doi: 10.1007/s40265-014-0178-8.
Singh S, Sadhukhan S, Sonawane A. 20 years since the approval of first EGFR-TKI, gefitinib: Insight and foresight. Biochim Biophys Acta BBA - Rev Cancer. 2023 Nov 1;1878(6):188967. doi: 10.1016/j.bbcan.2023.188967.
Cohen MH, Johnson JR, Chen YF, Sridhara R, Pazdur R. FDA Drug Approval Summary: Erlotinib (Tarceva®) Tablets. Oncologist. 2005 Aug 1;10(7):461–6. doi: 10.1634/theoncologist.10-7-461.
Yin Y, Shu Y, Zhu J, Li F, Li J. A real-world pharmacovigilance study of FDA Adverse Event Reporting System (FAERS) events for osimertinib. Sci Rep. 2022 Nov 15;12:19555. doi: 10.1038/s41598-022-23834-1.
Roskoski R. Orally effective FDA-approved protein kinase targeted covalent inhibitors (TCIs). Pharmacol Res. 2021 Mar;165:105422. doi: 10.1016/j.phrs.2021.105422.
Tan F, Shi Y, Wang Y, Ding L, Yuan X, Sun Y. Icotinib, a selective EGF receptor tyrosine kinase inhibitor, for the treatment of non-small-cell lung cancer. Future Oncol Lond Engl. 2015;11(3):385–97. doi: 10.2217/fon.14.249.
Ryan Q, Ibrahim A, Cohen MH, Johnson J, Ko C wen, Sridhara R, et al. FDA Drug Approval Summary: Lapatinib in Combination with Capecitabine for Previously Treated Metastatic Breast Cancer That Overexpresses HER-2. Oncologist. 2008 Oct 1;13(10):1114–9. doi: 10.1634/theoncologist.2008-0816.
Research C for DE and. FDA approves neratinib for extended adjuvant treatment of early stage HER2-positive breast cancer. FDA [Internet]. 2024 Aug 9; Available from: https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-neratinib-extended-adjuvant-treatment-early-stage-her2-positive-breast-cancer
Blair HA. Pyrotinib: First Global Approval. Drugs. 2018 Nov;78(16):1751–5. doi: 10.1007/s40265-018-0997-0.
Goodman VL, Rock EP, Dagher R, Ramchandani RP, Abraham S, Gobburu JVS, et al. Approval summary: sunitinib for the treatment of imatinib refractory or intolerant gastrointestinal stromal tumors and advanced renal cell carcinoma. Clin Cancer Res Off J Am Assoc Cancer Res. 2007 Mar 1;13(5):1367–73. doi: 10.1158/1078-0432.CCR-06-2328.
Kane RC, Farrell AT, Saber H, Tang S, Williams G, Jee JM, et al. Sorafenib for the treatment of advanced renal cell carcinoma. Clin Cancer Res Off J Am Assoc Cancer Res. 2006 Dec 15;12(24):7271–8. doi: 10.1158/1078-0432.CCR-06-1249.
Kane RC, Farrell AT, Madabushi R, Booth B, Chattopadhyay S, Sridhara R, et al. Sorafenib for the Treatment of Unresectable Hepatocellular Carcinoma. Oncologist. 2009 Jan 1;14(1):95–100. doi: 10.1634/theoncologist.2008-0185.
Sussman M, Munsell M, Valderrama A, Seal BS, Wen L. Estimating the Economic Impact of Sorafenib in Treatment of Locally Recurrent or Metastatic, Progressive, Differentiated Thyroid Carcinoma (DTC) That is Refractory to Radioactive Iodine (RAI) Treatment. Value Health. 2014 Nov;17(7):A621. doi: 10.1016/j.jval.2014.08.2200.
Thornton K, Kim G, Maher VE, Chattopadhyay S, Tang S, Moon YJ, et al. Vandetanib for the treatment of symptomatic or progressive medullary thyroid cancer in patients with unresectable locally advanced or metastatic disease: U.S. Food and Drug Administration drug approval summary. Clin Cancer Res Off J Am Assoc Cancer Res. 2012 Jul 15;18(14):3722–30. doi: 10.1158/1078-0432.CCR-12-0411.
Goel G. Evolution of regorafenib from bench to bedside in colorectal cancer: Is it an attractive option or merely a ‘me too’ drug? Cancer Manag Res. 2018;10:425–37. doi: 10.2147/CMAR.S88825.
Ferraro D, Zalcberg J. Regorafenib in gastrointestinal stromal tumors: clinical evidence and place in therapy. Ther Adv Med Oncol. 2014 Sep;6(5):222–8. doi: 10.1177/1758834014544892.
Pelosof L, Lemery S, Casak S, Jiang X, Rodriguez L, Pierre V, et al. Benefit‐Risk Summary of Regorafenib for the Treatment of Patients with Advanced Hepatocellular Carcinoma That Has Progressed on Sorafenib. Oncologist. 2018 Apr;23(4):496–500. doi: 10.1634/theoncologist.2017-0422.
Tyler T. Axitinib: Newly Approved for Renal Cell Carcinoma. J Adv Pract Oncol. 2012;3(5):333–5. doi: 10.6004/jadpro.2012.3.5.7.
Kazandjian D, Blumenthal GM, Chen HY, He K, Patel M, Justice R, et al. FDA approval summary: crizotinib for the treatment of metastatic non-small cell lung cancer with anaplastic lymphoma kinase rearrangements. Oncologist. 2014 Oct;19(10):e5-11. doi: 10.1634/theoncologist.2014-0241.
Markham A. Brigatinib: First Global Approval. Drugs. 2017 Jul;77(10):1131–5. doi: 10.1007/s40265-017-0776-3.
Liu G, Lam VK. Podcast on Lorlatinib as a First-Line Treatment Option for Patients with ALK-Positive Metastatic NSCLC with Brain Metastasis. Adv Ther. 2023 Oct;40(10):4117–26. doi: 10.1007/s12325-023-02606-x.
Markham A. Erdafitinib: First Global Approval. Drugs. 2019 Jun;79(9):1017–21. doi: 10.1007/s40265-019-01142-9.
Patel TH, Marcus L, Horiba MN, Donoghue M, Chatterjee S, Mishra-Kalyani PS, et al. FDA Approval Summary: Pemigatinib for Previously Treated, Unresectable Locally Advanced or Metastatic Cholangiocarcinoma with FGFR2 Fusion or Other Rearrangement. Clin Cancer Res Off J Am Assoc Cancer Res. 2023 Mar 1;29(5):838–42. doi: 10.1158/1078-0432.CCR-22-2036.
Cohen MH, Johnson JR, Pazdur R. U.S. Food and Drug Administration Drug Approval Summary: conversion of imatinib mesylate (STI571; Gleevec) tablets from accelerated approval to full approval. Clin Cancer Res Off J Am Assoc Cancer Res. 2005 Jan 1;11(1):12–9.
Kumar V, Doros L, Thompson M, Mushti SL, Charlab R, Spehalski EI, et al. FDA Approval Summary: Ripretinib for advanced gastrointestinal stromal tumor (GIST). Clin Cancer Res Off J Am Assoc Cancer Res. 2023 Jun 1;29(11):2020–4. doi: 10.1158/1078-0432.CCR-22-2400.
Research C for DE and. FDA approves avapritinib for gastrointestinal stromal tumor with a rare mutation. FDA [Internet]. 2020 Jan 9; Available from: https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-avapritinib-gastrointestinal-stromal-tumor-rare-mutation
Mathieu LN, Larkins E, Akinboro O, Roy P, Amatya AK, Fiero MH, et al. FDA Approval Summary: Capmatinib and Tepotinib for the Treatment of Metastatic NSCLC Harboring MET Exon 14 Skipping Mutations or Alterations. Clin Cancer Res Off J Am Assoc Cancer Res. 2022 Jan 15;28(2):249–54. doi: 10.1158/1078-0432.CCR-21-1566.
Duke ES, Bradford D, Marcovitz M, Amatya AK, Mishra-Kalyani PS, Nguyen E, et al. FDA Approval Summary: Selpercatinib for the treatment of advanced RET fusion-positive solid tumors. Clin Cancer Res Off J Am Assoc Cancer Res. 2023 Sep 15;29(18):3573–8. doi: 10.1158/1078-0432.CCR-23-0459.
Kim J, Bradford D, Larkins E, Pai-Scherf LH, Chatterjee S, Mishra-Kalyani PS, et al. FDA Approval Summary: Pralsetinib for the Treatment of Lung and Thyroid Cancers With RET Gene Mutations or Fusions. Clin Cancer Res Off J Am Assoc Cancer Res. 2021 Oct 15;27(20):5452–6. doi: 10.1158/1078-0432.CCR-21-0967.
Shuel SL. Targeted cancer therapies: Clinical pearls for primary care. Can Fam Physician Med Fam Can. 2022 Jul;68(7):515–8. doi: 10.46747/cfp.6807515.
Huang L, Jiang S, Shi Y. Tyrosine kinase inhibitors for solid tumors in the past 20 years (2001-2020). J Hematol OncolJ Hematol Oncol. 2020 Oct 27;13(1):143. doi: 10.1186/s13045-020-00977-0.
Nikolaou M, Pavlopoulou A, Georgakilas AG, Kyrodimos E. The challenge of drug resistance in cancer treatment: a current overview. Clin Exp Metastasis. 2018 Apr;35(4):309–18. doi: 10.1007/s10585-018-9903-0.
Khamisipour G, Jadidi-Niaragh F, Jahromi AS, Zandi K, Hojjat-Farsangi M. Mechanisms of tumor cell resistance to the current targeted-therapy agents. Tumour Biol J Int Soc Oncodevelopmental Biol Med. 2016 Aug;37(8):10021–39. doi: 10.1007/s13277-016-5059-1.
Potapova O, Laird AD, Nannini MA, Barone A, Li G, Moss KG, et al. Contribution of individual targets to the antitumor efficacy of the multitargeted receptor tyrosine kinase inhibitor SU11248. Mol Cancer Ther. 2006 May;5(5):1280–9. doi: 10.1158/1535-7163.MCT-03-0156.
Krug M, Hilgeroth A. Recent advances in the development of multi-kinase inhibitors. Mini Rev Med Chem. 2008 Nov;8(13):1312–27. doi: 10.2174/138955708786369591.
Grossman M, Adler E. Protein Kinase Inhibitors - Selectivity or Toxicity? In: Kumar Singh R, editor. Biochemistry [Internet]. IntechOpen; 2021. Available from: https://www.intechopen.com/books/protein-kinases-promising-targets-for-anticancer-drug-research/protein-kinase-inhibitors-selectivity-or-toxicity-
Hantschel O. Unexpected off-targets and paradoxical pathway activation by kinase inhibitors. ACS Chem Biol. 2015 Jan 16;10(1):234–45. doi: 10.1021/cb500886n.
Lamore SD, Kohnken RA, Peters MF, Kolaja KL. Cardiovascular Toxicity Induced by Kinase Inhibitors: Mechanisms and Preclinical Approaches. Chem Res Toxicol. 2020 Jan 21;33(1):125–36. doi: 10.1021/acs.chemrestox.9b00387.
Chen ZI, Ai DI. Cardiotoxicity associated with targeted cancer therapies. Mol Clin Oncol. 2016 May;4(5):675–81. doi: 10.3892/mco.2016.800.
González-Medina M, Miljković F, Haase GS, Drueckes P, Trappe J, Laufer S, et al. Promiscuity analysis of a kinase panel screen with designated p38 alpha inhibitors. Eur J Med Chem. 2020 Feb 1;187:112004. doi: 10.1016/j.ejmech.2019.112004.
Petrelli F, Borgonovo K, Cabiddu M, Lonati V, Barni S. Relationship between skin rash and outcome in non-small-cell lung cancer patients treated with anti-EGFR tyrosine kinase inhibitors: a literature-based meta-analysis of 24 trials. Lung Cancer Amst Neth. 2012 Oct;78(1):8–15. doi: 10.1016/j.lungcan.2012.06.009.
Jabbour E, Deininger M, Hochhaus A. Management of adverse events associated with tyrosine kinase inhibitors in the treatment of chronic myeloid leukemia. Leukemia. 2011 Feb;25(2):201–10. doi: 10.1038/leu.2010.215.
Shah DR, Shah RR, Morganroth J. Tyrosine kinase inhibitors: their on-target toxicities as potential indicators of efficacy. Drug Saf. 2013 Jun;36(6):413–26. doi: 10.1007/s40264-013-0050-x.
Lee WJ, Lee JL, Chang SE, Lee MW, Kang YK, Choi JH, et al. Cutaneous adverse effects in patients treated with the multitargeted kinase inhibitors sorafenib and sunitinib. Br J Dermatol. 2009 Nov;161(5):1045–51. doi: 10.1111/j.1365-2133.2009.09290.x.
Segaert S, Van Cutsem E. Clinical signs, pathophysiology and management of skin toxicity during therapy with epidermal growth factor receptor inhibitors. Ann Oncol Off J Eur Soc Med Oncol. 2005 Sep;16(9):1425–33. doi: 10.1093/annonc/mdi279.
Riccio G, Coppola C, Piscopo G, Capasso I, Maurea C, Esposito E, et al. Trastuzumab and target-therapy side effects: Is still valid to differentiate anthracycline Type I from Type II cardiomyopathies? Hum Vaccines Immunother. 2016 May 3;12(5):1124–31. doi: 10.1080/21645515.2015.1125056.
Totzeck M, Mincu RI, Rassaf T. Cardiovascular Adverse Events in Patients With Cancer Treated With Bevacizumab: A Meta-Analysis of More Than 20 000 Patients. J Am Heart Assoc. 2017 Aug 10;6(8):e006278. doi: 10.1161/JAHA.117.006278.
Herbrink M, Nuijen B, Schellens JHM, Beijnen JH. Variability in bioavailability of small molecular tyrosine kinase inhibitors. Cancer Treat Rev. 2015 May;41(5):412–22. doi: 10.1016/j.ctrv.2015.03.005.
Sarah A, Dondi E, De Francia S. Tyrosine kinase inhibitors: the role of pharmacokinetics and pharmacogenetics. Expert Opin Drug Metab Toxicol. 2023;19(11):733–9. doi: 10.1080/17425255.2023.2277758.
van Erp NP, Gelderblom H, Guchelaar HJ. Clinical pharmacokinetics of tyrosine kinase inhibitors. Cancer Treat Rev. 2009 Dec;35(8):692–706. doi: 10.1016/j.ctrv.2009.08.004.
Gay F, Oliva S, Petrucci MT, Conticello C, Catalano L, Corradini P, et al. Chemotherapy plus lenalidomide versus autologous transplantation, followed by lenalidomide plus prednisone versus lenalidomide maintenance, in patients with multiple myeloma: a randomised, multicentre, phase 3 trial. Lancet Oncol. 2015 Dec;16(16):1617–29. doi: 10.1016/S1470-2045(15)00389-7.
Zhao Q, Wu ZE, Li B, Li F. Recent advances in metabolism and toxicity of tyrosine kinase inhibitors. Pharmacol Ther. 2022 Sep;237:108256. doi: 10.1016/j.pharmthera.2022.108256.
Kaehler M, Cascorbi I. Pharmacogenomics of Impaired Tyrosine Kinase Inhibitor Response: Lessons Learned From Chronic Myelogenous Leukemia. Front Pharmacol. 2021;12:696960. doi: 10.3389/fphar.2021.696960.
Miura M. Therapeutic drug monitoring of imatinib, nilotinib, and dasatinib for patients with chronic myeloid leukemia. Biol Pharm Bull. 2015;38(5):645–54. doi: 10.1248/bpb.b15-00103.
Email this article (Login required) 
