Generic placeholder image

Letters in Drug Design & Discovery

Editor-in-Chief

ISSN (Print): 1570-1808
ISSN (Online): 1875-628X

Letter to the Editor

Lapatinib as a Dual Tyrosine Kinase Inhibitor Unexpectedly Activates Akt in MDA-MB-231 Triple-Negative Breast Cancer Cells

Author(s): Parham Jabbarzadeh Kaboli * and King-Hwa Ling

Volume 17, Issue 8, 2020

Page: [1060 - 1063] Pages: 4

DOI: 10.2174/1570180817666200212125658

Abstract

Background: MDA-MB-231 is a Triple-Negative Breast Cancer (TNBC) cell line, which is resistant to tyrosine kinase inhibitors, such as lapatinib. Lapatinib is well-recognized as an anti- EGFR and anti-Her2 compound. Here, we report one of the possible explanations for lapatinibresistance in TNBC cells, the most incurable type of breast cancer.

Methods: Using western blotting, we have observed that lapatinib-treated cells enhanced activation of Akt, an oncogenic protein activated at downstream of EGFR signaling.

Results: Anti-EGFR activity of Lapatinib would be counteracted with sustained activation of Akt. We found lapatinib-resistance in TNBC can be managed by administering Akt inhibitors. Further, lapatinib enhanced PI3K/Akt signaling is an alternative pathway to ensure the viability of MDAMB- 231 cells. There might also be unknown targets for lapatinib, which needs further investigation.

Conclusion: This observation opens up a new discussion on overcoming resistance to tyrosine kinase inhibitors, a key challenge in treating TNBC.

Keywords: Breast Cancer, TNBC, Lapatinib, Akt, Resistance, EGFR.

Graphical Abstract
[1]
Beretta, G.L. The molecular oncology of drug resistance: Targets, drugs and chemical biology. Curr. Med. Chem., 2019, 26(33), 6018-6019.
[http://dx.doi.org/10.2174/0929867326666190913194602] [PMID: 31518215]
[2]
Tang, K.D.; Ling, M-T. Targeting drug-resistant prostate cancer with dual PI3K/mTOR inhibition. Curr. Med. Chem., 2014, 21(26), 3048-3056.
[http://dx.doi.org/10.2174/0929867321666140414100127] [PMID: 24735368]
[3]
Liu, Z.; He, K.; Ma, Q.; Yu, Q.; Liu, C.; Ndege, I.; Wang, X.; Yu, Z. Autophagy inhibitor facilitates gefitinib sensitivity in vitro and in vivo by activating mitochondrial apoptosis in triple negative breast cancer. PLoS One, 2017, 12(5)e0177694
[http://dx.doi.org/10.1371/journal.pone.0177694] [PMID: 28531218]
[4]
Rosell, R.; Karachaliou, N.; Morales-Espinosa, D.; Costa, C.; Molina, M.A.; Sansano, I.; Gasco, A.; Viteri, S.; Massuti, B.; Wei, J.; González Cao, M.; Martínez Bueno, A. Adaptive resistance to targeted therapies in cancer. Transl. Lung Cancer Res., 2013, 2(3), 152-159.
[http://dx.doi.org/10.3978/j.issn.2218-6751.2012.12.08] [PMID: 25806228]
[5]
Jabbarzadeh Kaboli, P.; Leong, M.P-Y.; Ismail, P.; Ling, K-H. Antitumor effects of berberine against EGFR, ERK1/2, P38 and AKT in MDA-MB231 and MCF-7 breast cancer cells using molecular modelling and in vitro study. Pharmacol. Rep., 2019, 71(1), 13-23.
[http://dx.doi.org/10.1016/j.pharep.2018.07.005] [PMID: 30343043]
[6]
Meyer, A.S.; Miller, M.A.; Gertler, F.B.; Lauffenburger, D.A. The receptor AXL diversifies EGFR signaling and limits the response to EGFR-targeted inhibitors in triple-negative breast cancer cells. Sci. Signal., 2013, 6(287), ra66.
[http://dx.doi.org/10.1126/scisignal.2004155] [PMID: 23921085]
[7]
Su, C.M.; Chang, T.Y.; Hsu, H.P.; Lai, H.H.; Li, J.N.; Lyu, Y.J.; Kuo, K.T.; Huang, M.T.; Su, J.L.; Chen, P.S. A novel application of E1A in combination therapy with EGFR-TKI treatment in breast cancer. Oncotarget, 2016, 7(39), 63924-63936.
[http://dx.doi.org/10.18632/oncotarget.11737] [PMID: 27590506]
[8]
Lee, S.Y.; Meier, R.; Furuta, S.; Lenburg, M.E.; Kenny, P.A.; Xu, R.; Bissell, M.J. FAM83A confers EGFR-TKI resistance in breast cancer cells and in mice. J. Clin. Invest., 2012, 122(9), 3211-3220.
[http://dx.doi.org/10.1172/JCI60498] [PMID: 22886303]
[9]
Dwivedi, A.R.; Thakur, A.; Kumar, V.; Skvortsova, I.; Kumar, V. Targeting cancer stem cells pathways for the effective treatment of cancer. Curr. Drug Targets, 2019, 20, 1-21.
[http://dx.doi.org/10.2174/1389450120666190821160730] [PMID: 31433755]
[10]
Liu, C-Y.; Hu, M-H.; Hsu, C-J.; Huang, C-T.; Wang, D-S.; Tsai, W-C.; Chen, Y-T.; Lee, C-H.; Chu, P-Y.; Hsu, C-C.; Chen, M.H.; Shiau, C.W.; Tseng, L.M.; Chen, K.F. Lapatinib inhibits CIP2A/PP2A/p-Akt signaling and induces apoptosis in triple negative breast cancer cells. Oncotarget, 2016, 7(8), 9135-9149.
[http://dx.doi.org/10.18632/oncotarget.7035] [PMID: 26824320]
[11]
Spector, N.L.; Robertson, F.C.; Bacus, S.; Blackwell, K.; Smith, D.A.; Glenn, K.; Cartee, L.; Harris, J.; Kimbrough, C.L.; Gittelman, M.; Avisar, E.; Beitsch, P.; Koch, K.M. Lapatinib plasma and tumor concentrations and effects on HER receptor phosphorylation in tumor. PLoS One, 2015, 10(11)e0142845
[http://dx.doi.org/10.1371/journal.pone.0142845] [PMID: 26571496]
[12]
Yardley, D.A.; Hart, L.L.; Ward, P.J.; Wright, G.L.; Shastry, M.; Finney, L.; DeBusk, L.M.; Hainsworth, J.D. Cabazitaxel plus lapatinib as therapy for HER2+ metastatic breast cancer with intracranial metastases: Results of a dose-finding study. Clin. Breast Cancer, 2018, 18(5), e781-e787.
[http://dx.doi.org/10.1016/j.clbc.2018.03.004] [PMID: 29678476]
[13]
Wisinski, K.B.; Tevaarwerk, A.J.; Burkard, M.E.; Rampurwala, M.; Eickhoff, J.; Bell, M.C.; Kolesar, J.M.; Flynn, C.; Liu, G.; Phase, I.; Phase, I. Phase I study of an AKT inhibitor (MK-2206) combined with lapatinib in adult solid tumors followed by dose expansion in advanced HER2+ Breast Cancer. Clin. Cancer Res., 2016, 22(11), 2659-2667.
[http://dx.doi.org/10.1158/1078-0432.CCR-15-2365] [PMID: 27026198]
[14]
Ebelt, N.D.; Kaoud, T.S.; Edupuganti, R.; Van Ravenstein, S.; Dalby, K.N.; Van Den Berg, C.L. A c-Jun N-terminal kinase inhibitor, JNK-IN-8, sensitizes triple negative breast cancer cells to lapatinib. Oncotarget, 2017, 8(62), 104894-104912.
[http://dx.doi.org/10.18632/oncotarget.20581] [PMID: 29285221]
[15]
Zhang, H-S.; Du, G-Y.; Zhang, Z-G.; Zhou, Z.; Sun, H-L.; Yu, X-Y.; Shi, Y-T.; Xiong, D-N.; Li, H.; Huang, Y-H. NRF2 facilitates breast cancer cell growth via HIF1ɑ-mediated metabolic reprogramming. Int. J. Biochem. Cell Biol., 2018, 95, 85-92.
[http://dx.doi.org/10.1016/j.biocel.2017.12.016] [PMID: 29275212]
[16]
Seo, S.U.; Kim, T.H.; Kim, D.E.; Min, K-J.; Kwon, T.K. NOX4-mediated ROS production induces apoptotic cell death via down-regulation of c-FLIP and Mcl-1 expression in combined treatment with thioridazine and curcumin. Redox Biol., 2017, 13, 608-622.
[http://dx.doi.org/10.1016/j.redox.2017.07.017] [PMID: 28806703]
[17]
De Blasio, A.; Di Fiore, R.; Pratelli, G.; Drago-Ferrante, R.; Saliba, C.; Baldacchino, S.; Grech, G.; Scerri, C.; Vento, R.; Tesoriere, G. A loop involving NRF2, miR-29b-1-5p and AKT, regulates cell fate of MDA-MB-231 triple-negative breast cancer cells. J. Cell. Physiol., 2020, 235(2), 629-637.
[http://dx.doi.org/10.1002/jcp.29062] [PMID: 31313842]
[18]
Cen, J.; Zhang, L.; Liu, F.; Zhang, F.; Ji, B-S. Long-term alteration of reactive oxygen species led to multidrug resistance in MCF-7 cells. Oxid. Med. Cell. Longev., 2016, 20167053451
[http://dx.doi.org/10.1155/2016/7053451] [PMID: 28058088]
[19]
Zhang, R.; Qiao, H.; Chen, S.; Chen, X.; Dou, K.; Wei, L.; Zhang, J. Berberine reverses lapatinib resistance of HER2-positive breast cancer cells by increasing the level of ROS. Cancer Biol. Ther., 2016, 17(9), 925-934.
[http://dx.doi.org/10.1080/15384047.2016.1210728] [PMID: 27416292]
[20]
Young, A.; Lou, D.; McCormick, F. Oncogenic and wild-type Ras play divergent roles in the regulation of mitogen-activated protein kinase signaling. Cancer Discov., 2013, 3(1), 112-123.
[http://dx.doi.org/10.1158/2159-8290.CD-12-0231] [PMID: 23103856]

© 2024 Bentham Science Publishers | Privacy Policy