Anti‑Axl monoclonal antibodies attenuate the migration of MDA‑MB‑231 breast cancer cells

Chang,Hong; An,Ran; Li,Xinying; Lang,Xiaoling; Feng,Jiannan; Lv,Ming

doi:10.3892/ol.2021.13010

Anti‑Axl monoclonal antibodies attenuate the migration of MDA‑MB‑231 breast cancer cells

Authors:
- Hong Chang
- Ran An
- Xinying Li
- Xiaoling Lang
- Jiannan Feng
- Ming Lv
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Affiliations: Institute of Medical Technology, Suzhou Vocational Health College, Suzhou, Jiangsu 215009, P.R. China, College of Basic Medicine, Hebei University of Chinese Medicine, Shijiazhuang, Hebei 050200, P.R. China, State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, P.R. China, Beijing Key Laboratory of Therapeutic Gene Engineering Antibody, Beijing 100850, P.R. China
Published online on: August 27, 2021 https://doi.org/10.3892/ol.2021.13010
Article Number: 749
Copyright: © Chang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

The receptor tyrosine kinase, anexelekto (Axl) is involved in tumor cell growth, migration and invasion, and has been associated with chemotherapy resistance, which makes it an attractive target for cancer therapy. In total, six Axl‑targeted monoclonal antibodies (mAbs) and two antibody‑drug conjugates have been reported in the last 10 years, which have been shown to have bioactivity in inhibiting tumor cell proliferation and migration. The Axl external cell domain (Axl^‑ECD), consisting of 426 amino acids, has always been used as an antigen in the screening process for all six of these Axl‑targeted mAbs. However, the Axl functional domain, which interacts with its natural ligand, growth arrest‑specific protein 6 (Gas6), is only a small part of the Axl^‑ECD. Antibodies targeting the Axl functional domain may efficiently block Gas6‑Axl binding and attenuate its downstream signals and activities. To the best of our knowledge, no mAbs targeting the Axl functional domain have been reported. In the present study, a major Axl functional domain interacting with Gas6 was determined using bioinformatics and structural biology methods. In MDA‑MB‑231 breast cancer cell assays, anti‑Axl mAbs targeting this relatively specific Axl functional domain almost completely neutralized the stimulation of Gas6 in both Axl phosphorylation and cell migration assays, and showed similar activity to the positive control drug R428 (a small molecular tyrosine kinase inhibitor of Axl currently in phase II clinical trials) in the cell migration assay. Given the important role of Axl in tumor development and chemotherapy resistance, Axl‑targeted mAbs could be used to inhibit tumor cells directly, as well as reduce the development of chemotherapy resistance by blocking Axl activity. The application of Axl‑targeted mAbs combined with chemotherapy provides a promising treatment strategy for patients with tumors, particularly those with triple‑negative breast cancer, for whom no targeted therapy is currently available.

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1	Leconet W, Chentouf M, du Manoir S, Chevalier C, Sirvent A, Ait-Arsa I, Busson M, Jarlier M, Radosevic-Robin N, Theillet C, et al: Therapeutic activity of anti-AXL antibody against triple-negative breast cancer patient-derived xenografts and metastasis. Clin Cancer Res. 23:2806–2816. 2017. View Article : Google Scholar : PubMed/NCBI
2	Gay CM, Balaji K and Byers LA: Giving AXL the axe: Targeting AXL in human malignancy. Br J Cancer. 116:415–423. 2017. View Article : Google Scholar : PubMed/NCBI
3	Duan Y, Luo L, Qiao C, Li X, Wang J, Liu H, Zhou T, Shen B, Lv M and Feng J: A novel human anti-AXL monoclonal antibody attenuates tumour cell migration. Scand J Immunol. 90:e127772019. View Article : Google Scholar : PubMed/NCBI
4	Myers SH, Brunton VG and Unciti-Broceta A: AXL inhibitors in cancer: A Medicinal Chemistry Perspective. J Med Chem. 59:3593–3608. 2016. View Article : Google Scholar : PubMed/NCBI
5	Colavito SA: AXL as a target in breast cancer therapy. J Oncol. 2020:52919522020. View Article : Google Scholar : PubMed/NCBI
6	Leconet W, Larbouret C, Chardes T, Thomas G, Neiveyans M, Busson M, Jarlier M, Radosevic-Robin N, Pugniere M, Bernex F, et al: Preclinical validation of AXL receptor as a target for antibody-based pancreatic cancer immunotherapy. Oncogene. 33:5405–5414. 2014. View Article : Google Scholar : PubMed/NCBI
7	Iida S, Miki Y, Suzuki T, Mori K, Saito M, Niikawa H, Kondo T, Yamada-Okabe H and Sasano H: Activation of AXL and antitumor effects of a monoclonal antibody to AXL in lung adenocarcinoma. Anticancer Res. 34:1821–1827. 2014.PubMed/NCBI
8	Wei J, Sun H, Zhang A, Wu X, Li Y, Liu J, Duan Y, Xiao F, Wang H, Lv M, et al: A novel AXL chimeric antigen receptor endows T cells with anti-tumor effects against triple negative breast cancers. Cell Immunol. 331:49–58. 2018. View Article : Google Scholar : PubMed/NCBI
9	Oien DB, Garay T, Eckstein S and Chien J: Cisplatin and pemetrexed activate AXL and AXL inhibitor BGB324 enhances mesothelioma cell death from chemotherapy. Front Pharmacol. 8:9702018. View Article : Google Scholar : PubMed/NCBI
10	Hong J, Peng D, Chen Z, Sehdev V and Belkhiri A: ABL regulation by AXL promotes cisplatin resistance in esophageal cancer. Cancer Res. 73:331–340. 2013. View Article : Google Scholar : PubMed/NCBI
11	Hong CC, Lay JD, Huang JS, Cheng AL, Tang JL, Lin MT, Lai GM and Chuang SE: Receptor tyrosine kinase AXL is induced by chemotherapy drugs and overexpression of AXL confers drug resistance in acute myeloid leukemia. Cancer Lett. 268:314–324. 2008. View Article : Google Scholar : PubMed/NCBI
12	Li Y, Ye X, Tan C, Hongo JA, Zha J, Liu J, Kallop D, Ludlam MJ and Pei L: Axl as a potential therapeutic target in cancer: Role of Axl in tumor growth, metastasis and angiogenesis. Oncogene. 28:3442–3455. 2009. View Article : Google Scholar : PubMed/NCBI
13	Palisoul ML, Quinn JM, Schepers E, Hagemann IS, Guo L, Reger K, Hagemann AR, McCourt CK, Thaker PH, Powell MA, et al: Inhibition of the receptor tyrosine kinase AXL restores paclitaxel chemosensitivity in uterine serous cancer. Mol Cancer Ther. 16:2881–2891. 2017. View Article : Google Scholar : PubMed/NCBI
14	Ludwig KF, Du W, Sorrelle NB, Wnuk-Lipinska K, Topalovski M, Toombs JE, Cruz VH, Yabuuchi S, Rajeshkumar NV, Maitra A, et al: Small-molecule inhibition of axl targets tumor immune suppression and enhances chemotherapy in pancreatic cancer. Cancer Res. 78:246–255. 2018. View Article : Google Scholar : PubMed/NCBI
15	Shen Y, Chen X, He J, Liao D and Zu X: Axl inhibitors as novel cancer therapeutic agents. Life Sci. 198:99–111. 2018. View Article : Google Scholar : PubMed/NCBI
16	Falcone I, Conciatori F, Bazzichetto C, Bria E, Carbognin L, Malaguti P, Ferretti G, Cognetti F, Milella M and Ciuffreda L: AXL receptor in breast cancer: Molecular involvement and therapeutic limitations. Int J Mol Sci. 21:84192020. View Article : Google Scholar : PubMed/NCBI
17	Sheridan C: First Axl inhibitor enters clinical trials. Nat Biotechnol. 31:775–776. 2013. View Article : Google Scholar : PubMed/NCBI
18	Chen F, Song Q and Yu Q: Axl inhibitor R428 induces apoptosis of cancer cells by blocking lysosomal acidification and recycling independent of Axl inhibition. Am J Cancer Res. 8:1466–1482. 2018.PubMed/NCBI
19	Ye X, Li Y, Stawicki S, Couto S, Eastham-Anderson J, Kallop D, Weimer R, Wu Y and Pei L: An anti-Axl monoclonal antibody attenuates xenograft tumor growth and enhances the effect of multiple anticancer therapies. Oncogene. 29:5254–5264. 2010. View Article : Google Scholar : PubMed/NCBI
20	Koopman LA, Terp MG, Zom GG, Janmaat ML, Jacobsen K, Gresnigt-van den Heuvel E, Brandhorst M, Forssmann U, de Bree F, Pencheva N, et al: Enapotamab vedotin, an AXL-specific antibody-drug conjugate, shows preclinical antitumor activity in non-small cell lung cancer. JCI Insight. 4:e1281992019. View Article : Google Scholar : PubMed/NCBI
21	Ahnert JR, Taylor MH, O'Reilly E, Zhang J, Doebele R, Ben Y, Sharp L, Boyle WJ, Chang CY, Frey G, et al: A phase 1/2 dose-escalation and expansion study of a conditionally active anti-AXL humanized monoclonal antibody (BA3011) in patients with advanced solid tumors. J Clin Oncol. 36 (Suppl 15):TPS121262018. View Article : Google Scholar
22	Duan Y, Hu B, Qiao C, Luo L, Li X, Wang J, Liu H, Zhou T, Shen B, Lv M and Feng J: Engineered AXL^−ECD-Fc variants that abolish the AXL/Gas6 interaction suppress tumor cell migration. Oncol Lett. 17:5784–5792. 2019.PubMed/NCBI
23	Sasaki T, Knyazev PG, Clout NJ, Cheburkin Y, Gohring W, Ullrich A, Timpl R and Hohenester E: Structural basis for Gas6-Axl signalling. EMBO J. 25:80–87. 2006. View Article : Google Scholar : PubMed/NCBI
24	Suzuki K, Nakamura K, Kato K, Hamada H and Tsukamoto T: Exploration of target molecules for prostate cancer gene therapy. Prostate. 67:1163–1173. 2007. View Article : Google Scholar : PubMed/NCBI
25	Wilson C, Ye X, Pham T, Lin E, Chan S, McNamara E, Neve RM, Belmont L, Koeppen H, Yauch RL, et al: AXL inhibition sensitizes mesenchymal cancer cells to antimitotic drugs. Cancer Res. 74:5878–5890. 2014. View Article : Google Scholar : PubMed/NCBI
26	D'Alfonso TM, Hannah J, Chen Z, Liu Y, Zhou P and Shin SJ: Axl receptor tyrosine kinase expression in breast cancer. J Clin Pathol. 67:690–696. 2014. View Article : Google Scholar : PubMed/NCBI
27	Nakhjavani M, Hardingham JE, Palethorpe HM, Price TJ and Townsend AR: Druggable molecular targets for the treatment of triple negative breast cancer. J Breast Cancer. 22:341–361. 2019. View Article : Google Scholar : PubMed/NCBI
28	Tovey H and Cheang MCU: Identifying biomarkers to pair with targeting treatments within triple negative breast cancer for improved patient stratification. Cancers (Basel). 11:18642019. View Article : Google Scholar : PubMed/NCBI
29	Carey L, Winer E, Viale G, Cameron D and Gianni L: Triple-negative breast cancer: Disease entity or title of convenience? Nat Rev Clin Oncol. 7:683–692. 2010. View Article : Google Scholar : PubMed/NCBI
30	Ding L, Gu H, Xiong X, Ao H, Cao J, Lin W, Yu M, Lin J and Cui Q: MicroRNAs involved in carcinogenesis, prognosis, therapeutic resistance and applications in human triple-negative breast cancer. Cells. 8:14922019. View Article : Google Scholar : PubMed/NCBI
31	Kim KC, Baek SH and Lee C: Curcumin-induced downregulation of Axl receptor tyrosine kinase inhibits cell proliferation and circumvents chemoresistance in non-small lung cancer cells. Int J Oncol. 47:2296–2303. 2015. View Article : Google Scholar : PubMed/NCBI
32	Asiedu MK, Beauchamp-Perez FD, Ingle JN, Behrens MD, Radisky DC and Knutson KL: AXL induces epithelial-to-mesenchymal transition and regulates the function of breast cancer stem cells. Oncogene. 33:1316–1324. 2014. View Article : Google Scholar : PubMed/NCBI
33	Heckmann D, Maier P, Laufs S, Li L, Sleeman JP, Trunk MJ, Leupold JH, Wenz F, Zeller WJ, Fruehauf S and Allgayer H: The disparate twins: A comparative study of CXCR4 and CXCR7 in SDF-1α-induced gene expression, invasion and chemosensitivity of colon cancer. Clin Cancer Res. 20:604–616. 2014. View Article : Google Scholar : PubMed/NCBI
34	Sun ZG, Liu JH, Zhang JM and Qian Y: Research progress of Axl inhibitors. Curr Top Med Chem. 19:1338–1349. 2019. View Article : Google Scholar : PubMed/NCBI
35	Yang PW, Liu YC, Chang YH, Lin CC, Huang PM, Hua KT, Lee JM and Hsieh MS: Cabozantinib (XL184) and R428 (BGB324) inhibit the growth of esophageal squamous cell carcinoma (ESCC). Front Oncol. 9:11382019. View Article : Google Scholar : PubMed/NCBI
36	Zhang ZF, Lee JC, Lin L, Olivas V, Au V, LaFramboise T, Abdel-Rahman M, Wang X, Levine AD, Rho JK, et al: Activation of the AXL kinase causes resistance to EGFR-targeted therapy in lung cancer. Nat Genet. 44:852–860. 2012. View Article : Google Scholar : PubMed/NCBI
37	Schoumacher M and Burbridge M: Key Roles of AXL and MER receptor tyrosine kinases in resistance to multiple anticancer therapies. Curr Oncol Rep. 19:192017. View Article : Google Scholar : PubMed/NCBI
38	Liu L, Greger J, Shi H, Liu Y, Greshock J, Annan R, Halsey W, Sathe GM, Martin AM and Gilmer TM: Novel mechanism of lapatinib resistance in HER2-positive breast tumor cells: Activation of AXL. Cancer Res. 69:6871–6878. 2009. View Article : Google Scholar : PubMed/NCBI