Targeting Axl and Mer Kinases in Cancer

Verma, Anupam; Warner, Steven L.; Vankayalapati, Hariprasad; Bearss, David J.; Sharma, Sunil

doi:10.1158/1535-7163.mct-11-0116

Cited by 195 publications

(169 citation statements)

References 69 publications

(72 reference statements)

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“…Therefore, we assessed the expression of several RTKs to determine their theragnostic significance. AXL is an RTK associated with tumor invasion, angiogenesis, and metastasis 28 ; its expression correlates with a poor outcome in several malignancies, including MLPS, as reported here, and may be an attractive candidate for targeting given the availability of AXL inhibitors. AXL was expressed in almost all of our MLPS samples (97%); and, for the first time, we demonstrated that high AXL expression predicts a poor outcome in patients with MLPS (univariate analysis).…”

Section: Myxoid/round Cell Liposarcoma-related Biomarkersmentioning

confidence: 55%

Localized and metastatic myxoid/round cell liposarcoma

Hoffman

Ghadimi

Demicco

et al. 2013

Cancer

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BACKGROUND. Myxoid liposarcoma (MLPS), a disease especially of young adults with potential for local recurrence and metastasis, currently lacks solid prognostic factors and therapeutic targets. The authors of this report evaluated the natural history and outcome of patients with MLPS and commonly deregulated protein biomarkers. METHODS. Medical records were retrospectively reviewed for patients who presented to the authors' institution with localized (n ¼ 207) or metastatic (n ¼ 61) MLPS (1990MLPS ( to 2010. A tissue microarray of MLPS patient specimens (n ¼ 169) was constructed for immunohistochemical analysis of molecular markers. RESULTS. The 5-year and 10-year disease-specific survival rates among patients with localized disease were 93% and 87%, respectively; male gender, age >45 years, and recurrent tumor predicted poor outcome. The local recurrence rate was 7.4%, and the risk of local recurrence was associated with recurrent tumors and nonextremity disease location. Male gender was the main risk factor for metastatic disease, which occurred in 13% of patients. Forty percent of patients who had localized disease received chemotherapy, mostly in the neoadjuvant setting. Immunohistochemical analysis revealed significantly higher expression of C-X-C chemokine receptor type 4 (CXCR4) and platelet-derived growth factor beta (PDGFR-b) in metastatic lesions versus localized lesions. Tumors with a round cell phenotype expressed increased levels of CXCR4, p53, adipophilin, PDGFR-a, PDGFR-b, and vascular endothelial growth factor relative to myxoid phenotype. Only the receptor tyrosine kinase encoded by the AXL gene (AXL) was identified as a prognosticator of disease-specific survival in univariate analysis. CONCLUSIONS. In this study, the authors identified clinical and molecular outcome prognosticators for patients with MLPS as well as several potential therapeutic targets.

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Section: Myxoid/round Cell Liposarcoma-related Biomarkersmentioning

confidence: 55%

Localized and metastatic myxoid/round cell liposarcoma

Hoffman

Ghadimi

Demicco

et al. 2013

Cancer

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“…As shown in Fig. 1C, all 6 resistant clones express significantly higher levels of AXL, a tyrosine kinase receptor involved in promoting tumor cell growth, migration, invasion, metastasis, and angiogenesis (41,42). Clones TR13, TR14, TR19, and TR20 also showed reduced E-cadherin and increased N-cadherin levels (Fig.…”

Section: Potential Mechanisms Of Drug Resistance In Erlotinib-tr Clonesmentioning

confidence: 83%

Potential Advantages of CUDC-101, a Multitargeted HDAC, EGFR, and HER2 Inhibitor, in Treating Drug Resistance and Preventing Cancer Cell Migration and Invasion

Wang

Pursell

Samson

et al. 2013

Molecular Cancer Therapeutics

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CUDC-101 is a novel, small-molecule, anticancer agent targeting histone deacetylase (HDAC), EGF receptor (EGFR), and HER2. It is currently in phase I clinical development in patients with solid tumors. Previously, we reported that CUDC-101 has potent antiproliferative and proapoptotic activity in cultured tumor cells and in vivo xenograft models. We now show that cancer cells that have acquired resistance to single-target EGFR inhibitors through upregulation of AXL or loss of E-cadherin remain sensitive to CUDC-101, which inhibits MET-and AXL-mediated signaling, restores E-cadherin expression, and reduces cell migration. CUDC-101 also efficiently inhibited the proliferation of MET-overexpressing non-small cell lung cancer and gastric cancer cell lines and inhibited the migration and invasion of invasive tumor cells. Taken together, these results suggest that coupling HDAC and HER2 inhibitory activities to an EGFR inhibitor may potentially be effective in overcoming drug resistance and preventing cancer cell migration. Mol Cancer Ther; 12(6); 925-36. Ó2013 AACR.

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“…Notably, TAMs are overexpressed in a variety of cancers and possess a gain-of-function ability to activate oncogenic and survival signaling pathways (14). In many of these cancers, the level of overexpression positively correlates with chemo-resistance, metastasis, and poor survival outcomes (15).…”

Section: Receptor-tyrosine Kinases (Rtks)mentioning

confidence: 99%

Receptor Tyrosine Kinases, TYRO3, AXL, and MER, Demonstrate Distinct Patterns and Complex Regulation of Ligand-induced Activation

Tsou

Nguyen²,

Calarese³

et al. 2014

Journal of Biological Chemistry

185

203

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Background:The mechanisms by which ligands activate TAM receptors (TYRO3, AXL, and MER) are not well understood. Results:We created a series of TAM reporter cell lines and interrogated ligand-inducible TAM activation. Conclusion: TAMs are differentially activated by GAS6 and protein S and have distinct requirements for phosphatidylserine. Significance: Results reveal molecular mechanisms and rationale for non-overlapping functions of TAMs.

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Targeting Axl and Mer Kinases in Cancer

Cited by 195 publications

References 69 publications

Localized and metastatic myxoid/round cell liposarcoma

Localized and metastatic myxoid/round cell liposarcoma

Potential Advantages of CUDC-101, a Multitargeted HDAC, EGFR, and HER2 Inhibitor, in Treating Drug Resistance and Preventing Cancer Cell Migration and Invasion

Receptor Tyrosine Kinases, TYRO3, AXL, and MER, Demonstrate Distinct Patterns and Complex Regulation of Ligand-induced Activation

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