The receptor tyrosine kinase Axl in cancer: Biological functions and therapeutic implications

Paccez, Juliano D.; Vogelsang, Matjaž; Parker, M. Iqbal; Zerbini, Luiz F.

doi:10.1002/ijc.28246

Cited by 127 publications

(133 citation statements)

References 112 publications

(214 reference statements)

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“…Vice versa, low basal AKT phosphorylation levels indicate a higher sensitivity of the AKT sensor to upstream RTK inhibition. Axl was shown to influence AKT phosphorylation significantly as reviewed by Verma et al, 2011 and Pazzez et al, 2014 [7,41]. In the case of Axl-overexpressing cells, as used in the present study, this correlates with higher dependency on the upstream Axl-RTK signaling pathway.…”

Section: Discussionsupporting

confidence: 64%

801: Activation of HER3 interferes with antitumor effects of Axl receptor tyrosine kinase inhibitors − suggestion of combination therapy

Torka¹,

Pénzes²,

Baumann³

et al. 2014

European Journal of Cancer

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The Axl receptor tyrosine kinase (RTK) has been established as a strong candidate for targeted therapy of cancer. However, the benefits of targeted therapies are limited due to acquired resistance and activation of alternative RTKs. Therefore, we asked if cancer cells are able to overcome targeted Axl therapies. Here, we demonstrate that inhibition of Axl by short interfering RNA or the tyrosine kinase inhibitor (TKI) BMS777607 induces the expression of human epidermal growth factor receptor 3 (HER3) and the neuregulin 1(NRG1)-dependent phosphorylation of HER3 in MDA-MB231 and Ovcar8 cells. Moreover, analysis of 20 Axl-expressing cancer cell lines of different tissue origin indicates a low basal phosphorylation of RAC-α serine/threonine-protein kinase (AKT) as a general requirement for HER3 activation on Axl inhibition. Consequently, phosphorylation of AKT arises as an independent biomarker for Axl treatment. Additionally, we introduce phosphorylation of HER3 as an independent pharmacodynamic biomarker for monitoring of anti-Axl therapy response. Inhibition of cell viability by BMS777607 could be rescued by NRG1-dependent activation of HER3, suggesting an escape mechanism by tumor microenvironment. The Axl-TKI MPCD84111 simultaneously blocked Axl and HER2/3 signaling and thereby prohibited HER3 feedback activation. Furthermore, dual inhibition of Axl and HER2/3 using BMS777607 and lapatinib led to a significant inhibition of cell viability in Axl-expressing MDA-MB231 and Ovcar8 cells. Therefore, we conclude that, in patient cohorts with expression of Axl and low basal activity of AKT, a combined inhibition of Axl and HER2/3 kinase would be beneficial to overcome acquired resistance to Axl-targeted therapies.

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Section: Discussionsupporting

confidence: 64%

801: Activation of HER3 interferes with antitumor effects of Axl receptor tyrosine kinase inhibitors − suggestion of combination therapy

Torka¹,

Pénzes²,

Baumann³

et al. 2014

European Journal of Cancer

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“…These RTKs contribute to a carcinogenesis phenomenon via overexpression or ectopia, regulating processes such as migration, cell survival, and proliferation (3,5). They are involved in several cancers, such as pancreas, breast, prostate, nonsmall cell lung cancer (NSCLC), CML, and other cancers (6).…”

Section: Tam Family and Axlmentioning

confidence: 99%

Axl Kinase as a Key Target for Oncology: Focus on Small Molecule Inhibitors

Feneyrolles¹,

Spenlinhauer²,

Guiet³

et al. 2014

Molecular Cancer Therapeutics

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Receptor tyrosine kinases (RTK) are transmembrane receptors that regulate signal transduction in cells. As a member of the TAM (Tyro-3, Axl, Mer) RTK subfamily, Axl regulates key processes such as cell growth, migration, aggregation, and apoptosis through several pathways. Its overexpression/overactivation has been underlined in several conditions, especially cancers, and in both chemotherapy and targeted therapy sensitivity loss. In this review, we propose to highlight the therapeutic implication of Axl, starting with the pathways it regulates, validating its interest as a therapeutic target, and defining the tools available to develop strategies for its inhibition. We especially focus on small molecule inhibitors, their structure, inhibition profile, and development stages. Mol Cancer Ther; 13(9); 2141-8. Ó2014 AACR.

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“…Among the genes we identified in our microarray analysis, we chose to focus on AXL expression due to its established role in tumour cell invasion and metastasis, and because of its evident potential as a therapeutic target 13. When we examined the expression profiles of breast cancer cell lines individually, we found a clear trend of AXL upregulation in the basal B (triple-negative breast cancer) cells as compared to the luminal and basal A cell types (figure 1B).…”

Section: Resultsmentioning

confidence: 99%

“…Upregulation of AXL has since been observed in a number of cancers including colon,18 thyroid,19 breast,20 21 lung22 and liver,23 and has been shown to regulate numerous cellular processes relevant to cancer, such as cell survival, proliferation, migration and metastasis 13. Due to AXL 's involvement in cancer and the obvious appeal of receptor tyrosine kinases as drug targets, at least one specific small molecule kinase inhibitor (R428) and an inhibitory monoclonal antibody (YW327.6S2) have been developed to suppress AXL activity 24 25.…”

Section: Discussionmentioning

confidence: 99%

Axl receptor tyrosine kinase expression in breast cancer

et al. 2014

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Aims Triple-negative breast cancer comprises a clinically aggressive group of invasive carcinomas. We examined a published gene expression screen of a panel of breast cancer cell lines to identify a potential triple-negative breast cancer-specific gene signature, and attempted to verify our findings by performing immunohistochemical analysis on tissue microarrays containing a large cohort of invasive breast carcinomas. Methods The microarray dataset for a panel of human breast cancer cell lines was interrogated for triple-negative breast cancer-specific genes. Membranous immunohistochemical expression of the protein product of the AXL gene was assessed semiquantitatively in 569 invasive breast carcinomas grouped according to molecular subgroup by immunohistochemistry. Results AXL was significantly upregulated in triple-negative/basal B cell lines compared with luminal or basal A cell lines. No significant difference was observed in the level of immunohistochemical expression of Axl protein between triple-negative breast cancers and other molecular subgroups (p=0.257). Axl expression was significantly associated with lymphovascular invasion (LVI) in all subgroups combined (p=0.033), and within the luminal A (p=0.002) and triple-negative breast cancer subgroups (p=0.026). Conclusions Despite preferential upregulation of AXL in triple-negative/basal B cell lines, analysis of Axl protein expression in a large series of patients’ breast tumours revealed no association between Axl expression and triple-negative breast cancer or other subtype. The association of Axl expression with LVI supports previous work that implicates Axl as a promoter of invasiveness in breast cancer cell lines. Further studies are necessary to explore whether Axl expression of individual breast cancer tumours can be clinically useful.

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The receptor tyrosine kinase Axl in cancer: Biological functions and therapeutic implications

Cited by 127 publications

References 112 publications

801: Activation of HER3 interferes with antitumor effects of Axl receptor tyrosine kinase inhibitors − suggestion of combination therapy

801: Activation of HER3 interferes with antitumor effects of Axl receptor tyrosine kinase inhibitors − suggestion of combination therapy

Axl Kinase as a Key Target for Oncology: Focus on Small Molecule Inhibitors

Axl receptor tyrosine kinase expression in breast cancer

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