Effect of AXL on the epithelial-to-mesenchymal transition in non-small cell lung cancer

Ying, Xueming; Huang, Xueming; Huang, Peng; Yan, Shao-Cong

doi:10.3892/etm.2017.4532

Cited by 10 publications

(8 citation statements)

References 33 publications

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“…HMGA2, for instance, affects proliferation and metastasis by regulating TWIST, 42 FOSL1 regulates chemotherapy, exogenous SPARC promotes invasion and metastasis by activating SNAI1 21,42 and AXL activates TWIST to affect cell cycle. 23 A followup study could further substantiate TS as an integration point for these pathways resulting in a cumulative readout in terms of metastasis.…”

Section: Discussionmentioning

confidence: 96%

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Thymidylate synthase drives the phenotypes of epithelial-to-mesenchymal transition in non-small cell lung cancer

et al. 2020

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Background Epithelial-to-mesenchymal transition (EMT) enhances motility, stemness, chemoresistance and metastasis. Little is known about how various pathways coordinate to elicit EMT’s different functional aspects in non-small cell lung cancer (NSCLC). Thymidylate synthase (TS) has been previously correlated with EMT transcription factor ZEB1 in NSCLC and imparts resistance against anti-folate chemotherapy. In this study, we establish a functional correlation between TS, EMT, chemotherapy and metastasis and propose a network for TS mediated EMT. Methods Published datasets were analysed to evaluate the significance of TS in NSCLC fitness and prognosis. Promoter reporter assay was used to sort NSCLC cell lines in TSHIGH and TSLOW. Metastasis was assayed in a syngeneic mouse model. Results TS levels were prognostic and predicted chemotherapy response. Cell lines with higher TS promoter activity were more mesenchymal-like. RNA-seq identified EMT as one of the most differentially regulated pathways in connection to TS expression. EMT transcription factors HOXC6 and HMGA2 were identified as upstream regulator of TS, and AXL, SPARC and FOSL1 as downstream effectors. TS knock-down reduced the metastatic colonisation in vivo. Conclusion These results establish TS as a theranostic NSCLC marker integrating survival, chemo-resistance and EMT, and identifies a regulatory network that could be targeted in EMT-driven NSCLC.

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Section: Discussionmentioning

confidence: 96%

“…3B). Of these genes, SPARC, FOSL1 and AXL, that have an established role in EMT in NSCLC, [21][22][23] were strongly down-regulated at protein level in A549 cells with TS knockdown (Fig. 3d).…”

Section: Ts Is An Essential Nsclc Gene With Prognostic/predictive Powmentioning

confidence: 98%

Thymidylate synthase drives the phenotypes of epithelial-to-mesenchymal transition in non-small cell lung cancer

et al. 2020

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“…Finally, this study provides a perspective for a network that could integrate different signaling pathways to effectuate various aspects of cancer progression that are mediated by TS (Supp. (17,37) and AXL activates TWIST to affect cell cycle (19). A follow up study could further substantiate TS as an integration point for these pathways resulting in a cumulative readout in terms of metastasis.…”

Section: Discussionmentioning

confidence: 89%

“…Figure 3A). Of these genes, SPARC, FOSL1 and AXL, that have an established role in EMT in NSCLC (17)(18)(19), were strongly down regulated at protein level in A549 cells with TS knockdown (Figure 3D). Differentially expressed genes (DEGs) were used to derive a knockdown score, which predicted a worse survival associated with lower TS knockdown (higher TS levels, Figure 3E) and correlated with published EMT gene signature ( Figure 3F).…”

Section: Ts Regulates Emt Genes In Nsclcmentioning

confidence: 99%

Thymidylate synthase drives the phenotypes of epithelial-to-mesenchymal transition in non-small cell lung cancer

Siddiqui

Gollavilli

Ramesh

et al. 2020

Preprint

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Background. Epithelial-to-mesenchymal transition (EMT) enhances motility, stemness and chemoresistance of carcinomas and is an important determinant of metastasis. Little is known about how various pathways coordinate to elicit EMTs different functional aspects. Even lesser has been studied in this context in non-small cell lung cancer (NSCLC), where EMT is a key event during early tumorigenesis. Thymidylate synthase (TS), a proliferation enzyme, has been previously correlated with EMT transcription factor ZEB1 in NSCLC and is associated with resistance against anti-folate chemotherapy. In this study we establish a functional correlation between TS, EMT, chemotherapy and metastasis and identify a network that might propel the TS mediated EMT phenotype. Methods. Published datasets were analysed to evaluate significance of TS in NSCLC fitness and prognosis. mCherry based promoter reporter assay was used to sort Calu-1 and A549 NSCLC cells in TSHIGH and TSLOW. Metastatic potential of TS knock-down was assayed in syngeneic C57BL/6 mice. Results. Low TS levels were prognostic and predicted chemotherapy response. NSCLC cell lines with higher TS promoter activity were more mesenchymal-like. RNA-seq from these cells, and shRNA mediated TS knocked down cells, identified EMT as one of the most differentially regulated pathways. EMT transcription factors HOXC6 and HMGA2 were identified as upstream regulator of TS whereas, AXL, SPARC and FOSL1 were identified as downstream effectors. TS knock-down reduced the metastatic colonisation in vivo. Conclusion. These results establish the role of TS as a theranostic NSCLC marker integrating survival, chemo-resistance and EMT, and identifies a regulatory network that could be exploited to target EMT-driven NSCLC.

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“…Background AXL receptor tyrosine kinase (AXL) is a transmembrane protein that is over-expressed in a variety of cancer and immune cells. AXL signaling has been implicated in creating an immunosuppressive tumor microenvironment (TME) through both tumor-intrinsic and immunomodulatory mechanisms 1,2,3,4,5 promoting resistance to various therapies. 6,7,8,9 Methods Compound inhibition potency against the kinase activity of AXL and other kinases was determined by detecting phosphorylated substrate using homogeneous time-resolved fluorescence (HTRF).…”

mentioning

confidence: 99%

509 Potent and selective inhibition Of AXL receptor tyrosine kinase for the treatment of cancer

Paprcka¹,

Udyavar²,

Sridhar³

et al. 2020

Regular and Young Investigator Award Abstracts

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BackgroundAXL receptor tyrosine kinase (AXL) is a transmembrane protein that is over-expressed in a variety of cancer and immune cells. AXL signaling has been implicated in creating an immunosuppressive tumor microenvironment (TME) through both tumor-intrinsic and immunomodulatory mechanisms1,2,3,4,5 promoting resistance to various therapies.6,7,8,9MethodsCompound inhibition potency against the kinase activity of AXL and other kinases was determined by detecting phosphorylated substrate using homogeneous time-resolved fluorescence (HTRF). Binding affinity of inhibitor to intracellular AXL kinase was determined by monitoring displacement of a competitive fluorescent tracer using an AXL NanoBRET assay. Recombinant Gas6, cancer cell lines, whole blood or isolated cells from healthy donors were used to determine the reduction in AXL-mediated signaling in-vitro. PK/PD and anti-tumor effects of selected AXL inhibitors were evaluated in murine models.ResultsAXL is highly expressed on a subset of immune cells, including DC’s, NK cells and M2 macrophages as well as fibroblasts, which contribute to a blunted anti-tumor response. Consistent with these observations, AXL is strongly associated with increased infiltration of macrophages, exhausted NK and T-cells, as well as significantly increased CD73 expression in multiple cancer types in TCGA. Additionally, AXL expression is strongly and significantly correlated with epithelial-mesenchymal transition (EMT), which further generates an immunosuppressive TME and promotes resistance to immune, targeted and chemotherapies. High expression of AXL is also strongly associated with poor survival in NSCLC, pancreatic, breast, head & neck, stomach, colorectal, ovarian & prostate adenocarcinomas, especially in the metastatic setting. AXL inhibitors that exhibit high potency in both biochemical (IC <5nM) and cell-based (IC <25nM) assays in addition to good selectivity against closely related kinases MER and TYRO3 (>90x and >25x fold selectivity, respectively) as well as other kinases involved in downstream signaling such as PI3K have been developed. Initial studies in animal models indicate a favorable pharmacokinetic profile and anti-tumor efficacy.ConclusionsAXL is a promising therapeutic target involving both immunomodulatory and tumor-intrinsic mechanisms. AXL inhibition reduces the immunosuppressive TME, enables activation of an anti-tumor immune response and renders tumors more susceptible to previously resistant therapies. Highly potent and selective AXL inhibitors have been designed, displaying biological profiles superior to those of less-selective molecules currently advancing through clinical development.ReferencesGjerdrum C, Tiron C, Hoiby T, et al. Axl is an essential epithelial-to-mesenchymal transition-induced regulator of breast cancer metastasis and patient survival. PNAS 2010; 107(3):1124–1129.Ying X, Chen J, Huang X, Huang P, Yan S. Effect of AXL on the epithelial-to-mesenchymal transition in non-small cell lung cancer. Exp Ther Med 2017; 14:785–790.Tsukita Y, Fujino N, Miyauchi E, et al. Axl Kinase drives immune checkpoint and chemokine signalling pathways in lung adenocarcinomas. Molecular Cancer 2019;18:24.Terry S, Abdou A, Engelsen AST, et al. AXL targeting overcomes human lung cancer cell resistance to NK- and CTL-Mediated Cytotoxicity. Cancer Immunol Res 2019;7(11):1789–1802.Scutera S, Fraone T, Musso T, et al. Survival and migration of human dendritic cells are regulated by and IFN-alpha-Inducible Axl/Gas6 Pathway. J Immunol 2009; 183:3004–3013.Wilson C, Ye X, Pham T, et al. AXL Inhibition sensitizes mesenchymal cancer cells to antimitotic drugs. Cancer Res 2014;74(20):5878–5890.Ludwig KF, Du W, Sorrelle NB, et al. Small-Molecule Inhibition of Axl targets tumor immune suppression and enhances chemotherapy in pancreatic cancer. Cancer Res 2018; 78(1):246–255.Brand TM, Iida M, Stein AP, et al. AXL mediates resistance to cetuximab therapy. Cancer Res 2015;74(18):5152–5164.Guo Z, Li Y, Zhang D, Ma J. Axl Inhibition induces the antitumor response which can be further potentiated by PD-1 blockade in the mouse cancer models. Oncotarget 2017; 8(52):89761–89774

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Effect of AXL on the epithelial-to-mesenchymal transition in non-small cell lung cancer

Cited by 10 publications

References 33 publications

Thymidylate synthase drives the phenotypes of epithelial-to-mesenchymal transition in non-small cell lung cancer

Thymidylate synthase drives the phenotypes of epithelial-to-mesenchymal transition in non-small cell lung cancer

Thymidylate synthase drives the phenotypes of epithelial-to-mesenchymal transition in non-small cell lung cancer

509 Potent and selective inhibition Of AXL receptor tyrosine kinase for the treatment of cancer

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