TAMing resistance to multi-targeted kinase inhibitors through Axl and Met inhibition

Pinato, David J.; Stebbing, Justin

doi:10.1038/onc.2015.374

Cited by 18 publications

(20 citation statements)

References 25 publications

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“…These data were consistent with findings that AXL is a critical player in the metastatic potential and overall prognosis of numerous other solid cancers [7-11]. Binding of AXL to its only ligand, growth arrest specific gene-6 (GAS6), induces proliferation, survival, invasion, metastasis, avoidance of apoptosis, and angiogenesis in other tumor types [12, 13], though no activating mutation has been identified in AXL [14]. AXL acts through a number of downstream pathways, including the PI3K/AKT and Ras/ERK pathways [15].…”

Section: Introductionsupporting

confidence: 89%

Inhibition of the Receptor Tyrosine Kinase AXL Restores Paclitaxel Chemosensitivity in Uterine Serous Cancer

Palisoul

Quinn

Schepers

et al. 2017

Molecular Cancer Therapeutics

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Uterine serous cancer (USC) is aggressive, and the majority of recurrent cases are chemoresistant. Because the receptor tyrosine kinase AXL promotes invasion and metastasis of USC and is implicated in chemoresistance in other cancers, we assessed the role of AXL in paclitaxel resistance in USC, determined the mechanism of action, and sought to restore chemosensitivity by inhibiting AXL in vitro and in vivo. We used small hairpin RNAs and BGB324 to knock down and inhibit AXL. We assessed sensitivity of USC cell lines to paclitaxel and measured paclitaxel intracellular accumulation in vitro in the presence or absence of AXL. We also examined the role of the epithelial-mesenchymal transition in AXL-mediated paclitaxel resistance. Finally, we treated USC xenografts with paclitaxel, BGB324, or paclitaxel plus BGB324 and monitored tumor burden. AXL expression was higher in chemoresistant USC patient tumors and cell lines than in chemosensitive tumors and cell lines. Knockdown or inhibition of AXL increased sensitivity of USC cell lines to paclitaxel in vitro and increased cellular accumulation of paclitaxel. AXL promoted chemoresistance even in cells that underwent the epithelial-mesenchymal transition in vitro. Finally, in vivo studies of combination treatment with BGB324 and paclitaxel showed a greater than 51% decrease in tumor volume after 2 weeks of treatment when compared to no treatment or single agent treatments (P<0.001). Our results show that AXL expression mediates chemoresistance independent of EMT and prevents accumulation of paclitaxel. This study supports the continued investigation of AXL as a clinical target, particularly in chemoresistant USC.

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Section: Introductionsupporting

confidence: 89%

Inhibition of the Receptor Tyrosine Kinase AXL Restores Paclitaxel Chemosensitivity in Uterine Serous Cancer

Palisoul

Quinn

Schepers

et al. 2017

Molecular Cancer Therapeutics

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“…In most of these cases, aberrant overexpression of TAM receptors is observed; mutations in TAM receptors are an exception [19]. Mechanistically, TAM receptor signaling supports several key cellular events in the tumor, from cell growth and survival, to metastasis, epithelial-mesenchymal transition (EMT), and resistance to chemotherapy [20,22,23,24,122,123,124,125]. Importantly, experimental evidence demonstrates that TAM antagonism can efficiently revert these processes [22,126,127,128,129,130], underscoring the potential benefits of TAM inhibition for cancer therapy (Figure 3).…”

Section: Taming Anti-tumor Immunitymentioning

confidence: 99%

“…Notably, targeted inhibition of TAM signaling has proven to have robust anti-tumor efficacy in diverse experimental cancer settings. These results have encouraged a heated race in the development of novel and specific ways of inhibiting TAM signaling for use in cancer patients [24]. In fact, small-molecule kinase inhibitors, monoclonal antibodies, and soluble decoy TAM receptors are currently under development [25,26].…”

Section: Introductionmentioning

confidence: 99%

The Role of TAM Family Receptors in Immune Cell Function: Implications for Cancer Therapy

Paolino

Penninger

2016

Cancers

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The TAM receptor protein tyrosine kinases—Tyro3, Axl, and Mer—are essential regulators of immune homeostasis. Guided by their cognate ligands Growth arrest-specific gene 6 (Gas6) and Protein S (Pros1), these receptors ensure the resolution of inflammation by dampening the activation of innate cells as well as by restoring tissue function through promotion of tissue repair and clearance of apoptotic cells. Their central role as negative immune regulators is highlighted by the fact that deregulation of TAM signaling has been linked to the pathogenesis of autoimmune, inflammatory, and infectious diseases. Importantly, TAM receptors have also been associated with cancer development and progression. In a cancer setting, TAM receptors have a dual regulatory role, controlling the initiation and progression of tumor development and, at the same time, the associated anti-tumor responses of diverse immune cells. Thus, modulation of TAM receptors has emerged as a potential novel strategy for cancer treatment. In this review, we discuss our current understanding of how TAM receptors control immunity, with a particular focus on the regulation of anti-tumor responses and its implications for cancer immunotherapy.

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“…Axl is known to be indirectly under transcriptional control of VHL through hypoxia-inducible factors 27. Recent work has implicated Axl in the acquisition of resistance to antiangiogenic therapy, and revealed its contribution in driving metastatic spread and poorer survival 3 72. Recent large-scale phase III trials of TKI endowed with Axl inhibitory properties have confirmed Axl as a therapeutic target in RCC 73…”

Section: The Role Of Axl In Cancer Progressionmentioning

confidence: 99%

“…Evidence suggesting the oncogenic potential of Axl has been ever-present from the point of its initial isolation from chronic myelogenous leukaemia (CML) 1. Further work into the functionality of this gene has shown its mechanistic involvement in determining a wide variety of cancerous hallmarks including: proliferation, survival, evasion from apoptosis, enhanced angiogenesis, invasiveness and, more recently, resistance to targeted anticancer therapies 2 3. Furthermore, Axl has been shown to influence the clinical behaviour of a number of cancer histotypes, holding prognostic significance in breast, lung, ovarian, renal, gastrointestinal cancers as well as many other solid and haematopoietic malignancies.…”

Section: Introductionmentioning

confidence: 99%

Gene of the month:Axl

et al. 2016

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The interaction between Axl receptor tyrosine kinase and its main ligand Gas6 has been implicated in the progression of a wide number of malignancies. More recently, overexpression of Axl has emerged as a key molecular determinant underlying the development of acquired resistance to targeted anticancer agents. The activation of Axl is overexpression-dependent and controls a number of hallmarks of cancer progression including proliferation, migration, resistance to apoptosis and survival through a complex network of intracellular second messengers. Axl has been noted to influence clinically meaningful end points including metastatic recurrence and survival in the vast majority of tumour types. With Axl inhibitors having gained momentum as novel anticancer therapies, we provide an overview of the biological and clinical relevance of this molecular pathway, outlining the main directions of research.

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TAMing resistance to multi-targeted kinase inhibitors through Axl and Met inhibition

Cited by 18 publications

References 25 publications

Inhibition of the Receptor Tyrosine Kinase AXL Restores Paclitaxel Chemosensitivity in Uterine Serous Cancer

Inhibition of the Receptor Tyrosine Kinase AXL Restores Paclitaxel Chemosensitivity in Uterine Serous Cancer

The Role of TAM Family Receptors in Immune Cell Function: Implications for Cancer Therapy

Gene of the month:Axl

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