Theoretical and Natural Science
- The Open Access Proceedings Series for Conferences
Theoretical and Natural Science
Vol. 6, 03 August 2023
Open
Access | Article
A review of Lapatinib, a tyrosine kinase inhibitor, in HER2+ metastatic breast cancer treatment development
* Author to whom correspondence should be addressed.
Abstract
Metastatic breast cancer continues to have high mortality rates despite the numerous advances in drug therapy. Breast cancer patients have acquired resistance to current treatments, and severe adverse effects, such as cardiotoxicity caused by Trastuzumab, further contribute to the high mortality rate. Therefore, novel drugs with greater specificity and less severe adverse effects must be developed to combat the rise in treatment resistance. Lapatinib, a tyrosine kinase inhibitor, is an attractive drug of choice since lapatinib is not associated with cardiotoxicity, given its greater specificity to HER2 receptors compared to trastuzumab. This review provides a brief overview of tyrosine kinase inhibitors and their overall mechanism of action in treating HER2+ cancers. The study further summarizes the mechanism of action of Lapatinib, its pharmacokinetic properties, its clinical applications, the tools of the act of lapatinib resistance, and recent advances in developing derivatives of Lapatinib to combat lapatinib-acquired resistance.
Keywords
Lapatinib, breast cancer, HER2+
References
1. R. L. Siegel, K. D. Miller, H. E. Fuchs, and A. Jemal, “Cancer statistics, 2022,” CA: A Cancer Journal for Clinicians, vol. 72, no. 1, pp. 7–33, Jan. 2022, doi: https://doi.org/10.3322/caac.21708.
2. Patel, N. Unni, and Y. Peng, “The Changing Paradigm for the Treatment of HER2-Positive Breast Cancer,” Cancers, vol. 12, no. 8, p. 2081, Jul. 2020, doi: https://doi.org/10.3390/cancers12082081.
3. J. L. Hsu and M.-C. Hung, “The role of HER2, EGFR, and other receptor tyrosine kinases in breast cancer,” Cancer and Metastasis Reviews, vol. 35, no. 4, pp. 575–588, Dec. 2016, doi: https://doi.org/10.1007/s10555-016-9649-6.
4. P. Wee and Z. Wang, “Epidermal Growth Factor Receptor Cell Proliferation Signaling Pathways,” Cancers, vol. 9, no. 12, p. 52, May 2017.
5. E. Purba, E. Saita, and I. Maruyama, “Activation of the EGF Receptor by Ligand Binding and Oncogenic Mutations: The ‘Rotation Model,’” Cells, vol. 6, no. 2, p. 13, Jun. 2017, doi: https://doi.org/10.3390/cells6020013.
6. Q. Lv et al., “Molecular Mechanisms and Translational Therapies for Human Epidermal Receptor 2 Positive Breast Cancer,” International Journal of Molecular Sciences, vol. 17, no. 12, p. 2095, Dec. 2016, doi: https://doi.org/10.3390/ijms17122095.
7. N. Iqbal and N. Iqbal, “Human Epidermal Growth Factor Receptor 2 (HER2) in Cancers: Overexpression and Therapeutic Implications,” Molecular Biology International, vol. 2014, no. 1, pp. 1–9, 2014, doi: https://doi.org/10.1155/2014/852748.
8. H. Nitta et al., “The assessment of HER2 status in breast cancer: the past, the present, and the future,” Pathology International, vol. 66, no. 6, pp. 313–324, Apr. 2016, doi: https://doi.org/10.1111/pin.12407.
9. J. S. Ross, “Point: Fluorescence In Situ Hybridization Is the Preferred Approach over Immunohistochemistry for Determining HER2 Status,” Clinical Chemistry, vol. 57, no. 7, pp. 980–982, Jul. 2011, doi: https://doi.org/10.1373/clinchem.2010.160762.
10. U. Krishnamurti and J. F. Silverman, “HER2 in breast cancer: a review and update,” Advances in Anatomic Pathology, vol. 21, no. 2, pp. 100–107, Mar. 2014, doi: https://doi.org/10.1097/PAP.0000000000000015.
11. G. Griguolo, T. Pascual, M. V. Dieci, V. Guarneri, and A. Prat, “Interaction of host immunity with HER2-targeted treatment and tumor heterogeneity in HER2-positive breast cancer,” Journal for ImmunoTherapy of Cancer, vol. 7, no. 1, Mar. 2019, doi: https://doi.org/10.1186/s40425-019-0548-6.
12. V. Brower, “Cardiotoxicity Debated for Anthracyclines and Trastuzumab in Breast Cancer,” JNCI: Journal of the National Cancer Institute, vol. 105, no. 12, pp. 835–836, Jun. 2013, doi: https://doi.org/10.1093/jnci/djt161.
13. N. Spector, W. Xia, I. El-Hariry, Y. Yarden, and S. Bacus, “HER2 therapy. Small molecule HER-2 tyrosine kinase inhibitors,” Breast Cancer Research, vol. 9, no. 2, Mar. 2007, doi: https://doi.org/10.1186/bcr1652.
14. G. Iancu et al., “Tyrosine kinase inhibitors in breast cancer (Review),” Experimental and Therapeutic Medicine, vol. 23, no. 2, p. 114, Feb. 2022, doi: https://doi.org/10.3892/etm.2021.11037.
15. M. Segovia-Mendoza, M. E. González-González, D. Barrera, L. Díaz, and R. García-Becerra, “Efficacy and mechanism of action of the tyrosine kinase inhibitors gefitinib, lapatinib and neratinib in the treatment of HER2-positive breast cancer: preclinical and clinical evidence,” American journal of cancer research, vol. 5, no. 9, pp. 2531–61, 2015, Available: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4633889/
16. S. H. Ahn, E.-H. Jeong, T.-G. Lee, S. Y. Kim, H.-R. Kim, and C. H. Kim, “Gefitinib induces cytoplasmic translocation of the CDK inhibitor p27 and its binding to a cleaved intermediate of caspase 8 in non-small cell lung cancer cells,” Cellular Oncology (Dordrecht), vol. 37, no. 5, pp. 377–386, Oct. 2014, doi: https://doi.org/10.1007/s13402-014-0198-0.
17. P. Duda et al., “Targeting GSK3 and Associated Signaling Pathways Involved in Cancer,” Cells, vol. 9, no. 5, p. 1110, Apr. 2020, doi: https://doi.org/10.3390/cells9051110.
18. J. Baselga et al., “Phase II and tumor pharmacodynamic study of gefitinib in patients with advanced breast cancer,” Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology, vol. 23, no. 23, pp. 5323–5333, Aug. 2005, doi: https://doi.org/10.1200/JCO.2005.08.326.
19. A. Polychronis et al., “Preoperative gefitinib versus gefitinib and anastrozole in postmenopausal patients with oestrogen-receptor positive and epidermal-growth-factor-receptor-positive primary breast cancer: a double-blind placebo-controlled phase II randomised trial,” The Lancet Oncology, vol. 6, no. 6, pp. 383–391, Jun. 2005, doi: https://doi.org/10.1016/s1470-2045(05)70176-5.
20. A. Kalykaki, S. Agelaki, G. Kallergi, A. Xyrafas, D. Mavroudis, and V. Georgoulias, “Elimination of EGFR-expressing circulating tumor cells in patients with metastatic breast cancer treated with gefitinib,” Cancer Chemotherapy and Pharmacology, vol. 73, no. 4, pp. 685–693, Feb. 2014, doi: https://doi.org/10.1007/s00280-014-2387-y.
21. C. L. Arteaga et al., “A Phase I-II Study of Combined Blockade of the ErbB Receptor Network with Trastuzumab and Gefitinib in Patients with HER2 (ErbB2)-Overexpressing Metastatic Breast Cancer,” Clinical Cancer Research, vol. 14, no. 19, pp. 6277–6283, Sep. 2008, doi: https://doi.org/10.1158/1078-0432.ccr-08-0482.
22. G. Schaefer, L. Shao, K. Totpal, and R. W. Akita, “Erlotinib Directly Inhibits HER2 Kinase Activation and Downstream Signaling Events in Intact Cells Lacking Epidermal Growth Factor Receptor Expression,” Cancer Research, vol. 67, no. 3, pp. 1228–1238, Feb. 2007, doi: https://doi.org/10.1158/0008-5472.can-06-3493.
23. M. N. Dickler, M. A. Cobleigh, K. D. Miller, P. M. Klein, and E. P. Winer, “Efficacy and safety of erlotinib in patients with locally advanced or metastatic breast cancer,” Breast Cancer Research and Treatment, vol. 115, no. 1, pp. 115–121, May 2008, doi: https://doi.org/10.1007/s10549-008-0055-9.
24. M. Guix et al., “Short preoperative treatment with erlotinib inhibits tumor cell proliferation in hormone receptor-positive breast cancers,” Journal of clinical oncology, vol. 26, no. 6, pp. 897–906, Feb. 2008, doi: https://doi.org/10.1200/jco.2007.13.5939.
25. J. E. Frampton, “Lapatinib,” Drugs, vol. 69, no. 15, pp. 2125–2148, Oct. 2009, doi: https://doi.org/10.2165/11203240-000000000-00000.
26. D. W. Rusnak et al., “The Effects of the Novel, Reversible Epidermal Growth Factor Receptor/ErbB-2 Tyrosine Kinase Inhibitor, GW2016, on the Growth of Human Normal and Tumor-derived Cell Lines in Vitro and in Vivo,” Molecular Cancer Therapeutics, vol. 1, no. 2, pp. 85–94, Dec. 2001, Accessed: Feb. 04, 2023. [Online]. Available: https://aacrjournals.org/mct/article/1/2/85/233686/The-Effects-of-the-Novel-Reversible-Epidermal
27. J.-C. Xuhong, X.-W. Qi, Y. Zhang, and J. Jiang, “Mechanism, safety and efficacy of three tyrosine kinase inhibitors lapatinib, neratinib and pyrotinib in HER2-positive breast cancer,” American Journal of Cancer Research, vol. 9, no. 10, pp. 2103–2119, Oct. 2019, Available: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6834479/
28. J. W. Kim et al., “The growth inhibitory effect of lapatinib, a dual inhibitor of EGFR and HER2 tyrosine kinase, in gastric cancer cell lines,” Cancer Letters, vol. 272, no. 2, pp. 296–306, Dec. 2008, doi: https://doi.org/10.1016/j.canlet.2008.07.018.
29. B. Gril et al., “Effect of Lapatinib on the Outgrowth of Metastatic Breast Cancer Cells to the Brain,” JNCI Journal of the National Cancer Institute, vol. 100, no. 15, pp. 1092–1103, Jul. 2008, doi: https://doi.org/10.1093/jnci/djn216.
30. D. Zhang et al., “Activity of lapatinib is independent of EGFR expression level in HER2-overexpressing breast cancer cells,” Molecular Cancer Therapeutics, vol. 7, no. 7, pp. 1846–1850, Jul. 2008, doi: https://doi.org/10.1158/1535-7163.mct-08-0168.
31. R. Nahta, L. X. H. Yuan, Y. Du, and F. J. Esteva, “Lapatinib induces apoptosis in trastuzumab-resistant breast cancer cells: effects on insulin-like growth factor I signaling,” Molecular Cancer Therapeutics, vol. 6, no. 2, pp. 667–674, Feb. 2007, doi: https://doi.org/10.1158/1535-7163.MCT-06-0423.
32. H. A. Burris et al., “Phase I Safety, Pharmacokinetics, and Clinical Activity Study of Lapatinib (GW572016), a Reversible Dual Inhibitor of Epidermal Growth Factor Receptor Tyrosine Kinases, in Heavily Pretreated Patients With Metastatic Carcinomas,” Journal of Clinical Oncology, vol. 23, no. 23, pp. 5305–5313, Aug. 2005, doi: https://doi.org/10.1200/jco.2005.16.584.
33. J. W. Polli et al., “An Unexpected Synergist Role of P-Glycoprotein and Breast Cancer Resistance Protein on the Central Nervous System Penetration of the Tyrosine Kinase Inhibitor Lapatinib (N-{3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-[5-({[2-(methylsulfonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine; GW572016),” Drug Metabolism and Disposition, vol. 37, no. 2, pp. 439–442, Feb. 2009, doi: https://doi.org/10.1124/dmd.108.024646.
34. D. A. Smith, K. M. Koch, N. Arya, C. J. Bowen, J. M. Herendeen, and A. Beelen, “Effects of ketoconazole and carbamazepine on lapatinib pharmacokinetics in healthy subjects,” British Journal of Clinical Pharmacology, vol. 67, no. 4, pp. 421–426, Apr. 2009, doi: https://doi.org/10.1111/j.1365-2125.2009.03370.x.
35. F. L. Opdam, H. Guchelaar, J. H. Beijnen, and J. H. M. Schellens, “Lapatinib for Advanced or Metastatic Breast Cancer,” The Oncologist, vol. 17, no. 4, pp. 536–542, Apr. 2012, doi: https://doi.org/10.1634/theoncologist.2011-0461.
36. G. Capri et al., “An open-label expanded access study of lapatinib and capecitabine in patients with HER2-overexpressing locally advanced or metastatic breast cancer,” Annals of Oncology, vol. 21, no. 3, pp. 474–480, Mar. 2010, doi: https://doi.org/10.1093/annonc/mdp373.
37. “European Medicines Agency Tyverb® Summary of Product Characteristics.” Accessed: Feb. 04, 2023. [Online]. Available: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000795/WC500044957.pdf.
38. H. D. Choi and M. J. Chang, “Cardiac toxicities of lapatinib in patients with breast cancer and other HER2-positive cancers: a meta-analysis,” Breast Cancer Research and Treatment, vol. 166, no. 3, pp. 927–936, Dec. 2017, doi: https://doi.org/10.1007/s10549-017-4460-9.
39. V. D’Amato et al., “Mechanisms of lapatinib resistance in HER2-driven breast cancer,” Cancer Treatment Reviews, vol. 41, no. 10, pp. 877–883, Dec. 2015, doi: https://doi.org/10.1016/j.ctrv.2015.08.001.
40. J. T. Garrett et al., “Transcriptional and posttranslational up-regulation of HER3 (ErbB3) compensates for inhibition of the HER2 tyrosine kinase,” Proceedings of the National Academy of Sciences of the United States of America, vol. 108, no. 12, pp. 5021–5026, Mar. 2011, doi: https://doi.org/10.1073/pnas.1016140108.
41. L. Liu et al., “Novel Mechanism of Lapatinib Resistance in HER2-Positive Breast Tumor Cells: Activation of AXL,” Cancer Research, vol. 69, no. 17, pp. 6871–6878, Aug. 2009, doi: https://doi.org/10.1158/0008-5472.can-08-4490.
42. B. N. Rexer et al., “Phosphoproteomic mass spectrometry profiling links Src family kinases to escape from HER2 tyrosine kinase inhibition,” Oncogene, vol. 30, no. 40, pp. 4163–4174, Apr. 2011, doi: https://doi.org/10.1038/onc.2011.130.
43. B. Xu et al., “Association of phosphatase and tensin homolog low and phosphatidylinositol 3-kinase catalytic subunit alpha gene mutations on outcome in human epidermal growth factor receptor 2-positive metastatic breast cancer patients treated with first-line lapatinib plus paclitaxel or paclitaxel alone,” Breast Cancer Research, vol. 16, no. 4, Jul. 2014, doi: https://doi.org/10.1186/s13058-014-0405-y.
44. D. R. Boulbes et al., “HER family kinase domain mutations promote tumor progression and can predict response to treatment in human breast cancer,” Molecular Oncology, vol. 9, no. 3, pp. 586–600, Nov. 2014, doi: https://doi.org/10.1016/j.molonc.2014.10.011.
45. D. Cameron, M. Casey, C. Oliva, B. Newstat, B. Imwalle, and C. E. Geyer, “Lapatinib plus capecitabine in women with HER-2-positive advanced breast cancer: final survival analysis of a phase III randomized trial,” The Oncologist, vol. 15, no. 9, pp. 924–934, 2010, doi: https://doi.org/10.1634/theoncologist.2009-0181.
46. X. Gui, H. Li, Y. Yan, and R. Zhang, “Efficacy of lapatinib combined with capecitabine in patients with HER2‑positive metastatic breast cancer in a real‑world study,” Oncology Letters, vol. 20, no. 6, pp. 1–1, Oct. 2020, doi: https://doi.org/10.3892/ol.2020.12241.
47. C. Saura et al., “Neratinib Plus Capecitabine Versus Lapatinib Plus Capecitabine in HER2-Positive Metastatic Breast Cancer Previously Treated With ≥ 2 HER2-Directed Regimens: Phase III NALA Trial,” Journal of Clinical Oncology, vol. 38, no. 27, pp. 3138–3149, Sep. 2020, doi: https://doi.org/10.1200/jco.20.00147.
48. M. F. Rimawi et al., “Multicenter Phase II Study of Neoadjuvant Lapatinib and Trastuzumab With Hormonal Therapy and Without Chemotherapy in Patients With Human Epidermal Growth Factor Receptor 2–Overexpressing Breast Cancer: TBCRC 006,” Journal of Clinical Oncology, vol. 31, no. 14, pp. 1726–1731, May 2013, doi: https://doi.org/10.1200/jco.2012.44.8027.
49. A. Elkamhawy et al., “Design, Synthesis, Biological Evaluation, and Molecular Dynamics Studies of Novel Lapatinib Derivatives,” Pharmaceuticals, vol. 16, no. 1, p. 43, Jan. 2023, doi: https://doi.org/10.3390/
50. M. Bello, C. Guadarrama-García, and R. A. Rodriguez-Fonseca, “Dissecting the molecular recognition of dual lapatinib derivatives for EGFR/HER2,” Journal of Computer-Aided Molecular Design, vol. 34, no. 3, pp. 293–303, Dec. 2019, doi: https://doi.org/10.1007/s10822-019-00270-4.
Data Availability
The datasets used and/or analyzed during the current study will be available from the authors upon reasonable request.
This work is licensed under a Creative Commons Attribution-ShareAlike 4.0 International License. Authors who publish this series agree to the following terms:
1. Authors retain copyright and grant the series right of first publication with the work simultaneously licensed under a Creative Commons Attribution License that allows others to share the work with an acknowledgment of the work's authorship and initial publication in this series.
2. Authors are able to enter into separate, additional contractual arrangements for the non-exclusive distribution of the series's published version of the work (e.g., post it to an institutional repository or publish it in a book), with an acknowledgment of its initial publication in this series.
3. Authors are permitted and encouraged to post their work online (e.g., in institutional repositories or on their website) prior to and during the submission process, as it can lead to productive exchanges, as well as earlier and greater citation of published work (See Open Access Instruction).
- Volume Title
- Proceedings of the International Conference on Modern Medicine and Global Health (ICMMGH 2023)
- ISBN (Print)
- 978-1-915371-65-2
- ISBN (Online)
- 978-1-915371-66-9
- Published Date
- 03 August 2023
- Series
- Theoretical and Natural Science
- ISSN (Print)
- 2753-8818
- ISSN (Online)
- 2753-8826
- DOI
- 10.54254/2753-8818/6/20230205
- Copyright
- 03 August 2023
- Open Access
- This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited