AXL Is a Logical Molecular Target in Head and Neck Squamous Cell Carcinoma

Overview

Journal Clin Cancer Res

Specialty Oncology

Date 2015 Mar 14

PMID 25767293

Citations 70

Authors

Toni M Brand

Mari Iida

Andrew P Stein

Kelsey L Corrigan

Cara M Braverman

John P Coan

Hannah E Pearson

Harsh Bahrar

Tyler L Fowler

Bryan P Bednarz

Sandeep Saha

David Yang

Parkash S Gill

Mark W Lingen

Vassiliki Saloura

Victoria M Villaflor

Ravi Salgia

Randall J Kimple

Deric L Wheeler

Affiliations

Soon will be listed here.

Abstract

Purpose: Head and neck squamous cell carcinoma (HNSCC) represents the eighth most common malignancy worldwide. Standard-of-care treatments for patients with HNSCC include surgery, radiation, and chemotherapy. In addition, the anti-EGFR monoclonal antibody cetuximab is often used in combination with these treatment modalities. Despite clinical success with these therapeutics, HNSCC remains a difficult malignancy to treat. Thus, identification of new molecular targets is critical.

Experimental Design: In the current study, the receptor tyrosine kinase AXL was investigated as a molecular target in HNSCC using established cell lines, HNSCC patient-derived xenografts (PDX), and human tumors. HNSCC dependency on AXL was evaluated with both anti-AXL siRNAs and the small-molecule AXL inhibitor R428. Furthermore, AXL inhibition was evaluated with standard-of-care treatment regimens used in HNSCC.

Results: AXL was found to be highly overexpressed in several models of HNSCC, where AXL was significantly associated with higher pathologic grade, presence of distant metastases, and shorter relapse-free survival in patients with HNSCC. Further investigations indicated that HNSCC cells were reliant on AXL for cellular proliferation, migration, and invasion. In addition, targeting AXL increased HNSCC cell line sensitivity to chemotherapy, cetuximab, and radiation. Moreover, radiation-resistant HNSCC cell line xenografts and PDXs expressed elevated levels of both total and activated AXL, indicating a role for AXL in radiation resistance.

Conclusions: This study provides evidence for the role of AXL in HNSCC pathogenesis and supports further preclinical and clinical evaluation of anti-AXL therapeutics for the treatment of patients with HNSCC.

Citing Articles

AXL signaling in cancer: from molecular insights to targeted therapies.

Yadav M, Sharma A, Patne K, Tabasum S, Suryavanshi J, Rawat L Signal Transduct Target Ther. 2025; 10(1):37.

PMID: 39924521 PMC: 11808115. DOI: 10.1038/s41392-024-02121-7.

From Bench to Bedside: A Team's Approach to Multidisciplinary Strategies to Combat Therapeutic Resistance in Head and Neck Squamous Cell Carcinoma.

Crossman B, Harmon R, Kostecki K, McDaniel N, Iida M, Corday L J Clin Med. 2024; 13(20).

PMID: 39457986 PMC: 11508784. DOI: 10.3390/jcm13206036.

AXL as immune regulator and therapeutic target in Acute Myeloid Leukemia: from current progress to novel strategies.

Vandewalle N, De Beule N, De Becker A, de Bruyne E, Menu E, Vanderkerken K Exp Hematol Oncol. 2024; 13(1):99.

PMID: 39367387 PMC: 11453060. DOI: 10.1186/s40164-024-00566-8.

AXL inhibition prevents RPA2/CHK1-mediated homologous recombination to increase PARP inhibitor sensitivity in hepatocellular carcinoma.

Li K, Deng L, Xue L, Tan C, Yao S Heliyon. 2024; 10(17):e36283.

PMID: 39281567 PMC: 11399589. DOI: 10.1016/j.heliyon.2024.e36283.

Aberrant activation of AXL may drive progression of squamous cell carcinoma in CLL patients: a mechanistic study with clinical implications.

Sinha S, Guo R, Del Busso M, Han W, Boysen J, Wellik L Br J Cancer. 2024; 131(3):589-600.

PMID: 38886556 PMC: 11300914. DOI: 10.1038/s41416-024-02752-1.

References

Feneyrolles C, Spenlinhauer A, Guiet L, Fauvel B, Dayde-Cazals B, Warnault P . Axl kinase as a key target for oncology: focus on small molecule inhibitors. Mol Cancer Ther. 2014; 13(9):2141-8. DOI: 10.1158/1535-7163.MCT-13-1083. View

Han J, Tian R, Yong B, Luo C, Tan P, Shen J . Gas6/Axl mediates tumor cell apoptosis, migration and invasion and predicts the clinical outcome of osteosarcoma patients. Biochem Biophys Res Commun. 2013; 435(3):493-500. DOI: 10.1016/j.bbrc.2013.05.019. View

Meyn R, Munshi A, Haymach J, Milas L, Ang K . Receptor signaling as a regulatory mechanism of DNA repair. Radiother Oncol. 2009; 92(3):316-22. PMC: 2754282. DOI: 10.1016/j.radonc.2009.06.031. View

Peng Y, Zhang Q, Nagasawa H, Okayasu R, Liber H, Bedford J . Silencing expression of the catalytic subunit of DNA-dependent protein kinase by small interfering RNA sensitizes human cells for radiation-induced chromosome damage, cell killing, and mutation. Cancer Res. 2002; 62(22):6400-4. View

Giles K, Kalinowski F, Candy P, Epis M, Zhang P, Redfern A . Axl mediates acquired resistance of head and neck cancer cells to the epidermal growth factor receptor inhibitor erlotinib. Mol Cancer Ther. 2013; 12(11):2541-58. DOI: 10.1158/1535-7163.MCT-13-0170. View

Linger R, Cohen R, Cummings C, Sather S, Migdall-Wilson J, Middleton D . Mer or Axl receptor tyrosine kinase inhibition promotes apoptosis, blocks growth and enhances chemosensitivity of human non-small cell lung cancer. Oncogene. 2012; 32(29):3420-31. PMC: 3502700. DOI: 10.1038/onc.2012.355. View

Fakhry C, Westra W, Li S, Cmelak A, Ridge J, Pinto H . Improved survival of patients with human papillomavirus-positive head and neck squamous cell carcinoma in a prospective clinical trial. J Natl Cancer Inst. 2008; 100(4):261-9. DOI: 10.1093/jnci/djn011. View

Brand T, Iida M, Stein A, Corrigan K, Braverman C, Luthar N . AXL mediates resistance to cetuximab therapy. Cancer Res. 2014; 74(18):5152-64. PMC: 4167493. DOI: 10.1158/0008-5472.CAN-14-0294. View

Li C, Iida M, Dunn E, Ghia A, Wheeler D . Nuclear EGFR contributes to acquired resistance to cetuximab. Oncogene. 2009; 28(43):3801-13. PMC: 2900381. DOI: 10.1038/onc.2009.234. View

10.

Chou T . Theoretical basis, experimental design, and computerized simulation of synergism and antagonism in drug combination studies. Pharmacol Rev. 2006; 58(3):621-81. DOI: 10.1124/pr.58.3.10. View

11.

Chou T, Talalay P . Quantitative analysis of dose-effect relationships: the combined effects of multiple drugs or enzyme inhibitors. Adv Enzyme Regul. 1984; 22:27-55. DOI: 10.1016/0065-2571(84)90007-4. View

12.

Iida M, Brand T, Campbell D, Li C, Wheeler D . Yes and Lyn play a role in nuclear translocation of the epidermal growth factor receptor. Oncogene. 2012; 32(6):759-67. PMC: 3381861. DOI: 10.1038/onc.2012.90. View

13.

Posner M, Haddad R, Wirth L, Norris C, Goguen L, Mahadevan A . Induction chemotherapy in locally advanced squamous cell cancer of the head and neck: evolution of the sequential treatment approach. Semin Oncol. 2004; 31(6):778-85. DOI: 10.1053/j.seminoncol.2004.09.007. View

14.

Linger R, Keating A, Earp H, Graham D . TAM receptor tyrosine kinases: biologic functions, signaling, and potential therapeutic targeting in human cancer. Adv Cancer Res. 2008; 100:35-83. PMC: 3133732. DOI: 10.1016/S0065-230X(08)00002-X. View

15.

Toulany M, Kehlbach R, Florczak U, Sak A, Wang S, Chen J . Targeting of AKT1 enhances radiation toxicity of human tumor cells by inhibiting DNA-PKcs-dependent DNA double-strand break repair. Mol Cancer Ther. 2008; 7(7):1772-81. DOI: 10.1158/1535-7163.MCT-07-2200. View

16.

Meyer A, Miller M, Gertler F, Lauffenburger D . 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. PMC: 3947921. DOI: 10.1126/scisignal.2004155. View

17.

Fowler T, Fulkerson R, Micka J, Kimple R, Bednarz B . A novel high-throughput irradiator for in vitro radiation sensitivity bioassays. Phys Med Biol. 2014; 59(6):1459-70. PMC: 4036445. DOI: 10.1088/0031-9155/59/6/1459. View

18.

Rho J, Choi Y, Kim S, Kim T, Choi E, Yoon S . MET and AXL inhibitor NPS-1034 exerts efficacy against lung cancer cells resistant to EGFR kinase inhibitors because of MET or AXL activation. Cancer Res. 2013; 74(1):253-62. DOI: 10.1158/0008-5472.CAN-13-1103. View

19.

Ye X, Li Y, Stawicki S, Couto S, Eastham-Anderson J, Kallop D . An anti-Axl monoclonal antibody attenuates xenograft tumor growth and enhances the effect of multiple anticancer therapies. Oncogene. 2010; 29(38):5254-64. DOI: 10.1038/onc.2010.268. View

20.

Basu D, Nguyen T, Montone K, Zhang G, Wang L, Diehl J . Evidence for mesenchymal-like sub-populations within squamous cell carcinomas possessing chemoresistance and phenotypic plasticity. Oncogene. 2010; 29(29):4170-82. PMC: 3039880. DOI: 10.1038/onc.2010.170. View