Role of the Receptor Tyrosine Kinase Axl and its Targeting in Cancer Cells

Corno, Cristina; Gatti, Laura; Lanzi, Cinzia; Zaffaroni, Nadia; Colombo, Diego; Perego, Paola

doi:10.2174/0929867323666160405112954

Cited by 37 publications

(30 citation statements)

References 103 publications

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“…The AXL gene is located on chromosome 19q13.2; encoded by 20 exons. The protein structure consists of an extracellular domain consisting of a combination of two IgG like domains and two fibronectin type III repeats; a conserved intracellular kinase domain and a transmembrane domain [162,163]. Even though all three TAMS have transforming potential, the aberrant overexpression of Axl is associated with cancer progression, drug resistance and supports tumor immune escape in several cancers including melanoma [164][165][166][167][168][169][170][171][172].…”

Section: Axl Inhibitorsmentioning

confidence: 99%

Current Advances in the Treatment of BRAF-Mutant Melanoma

Patel

Yacoub

Mishra

et al. 2020

Cancers

125

102

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Melanoma is the most lethal form of skin cancer. Melanoma is usually curable with surgery if detected early, however, treatment options for patients with metastatic melanoma are limited and the five-year survival rate for metastatic melanoma had been 15–20% before the advent of immunotherapy. Treatment with immune checkpoint inhibitors has increased long-term survival outcomes in patients with advanced melanoma to as high as 50% although individual response can vary greatly. A mutation within the MAPK pathway leads to uncontrollable growth and ultimately develops into cancer. The most common driver mutation that leads to this characteristic overactivation in the MAPK pathway is the B-RAF mutation. Current combinations of BRAF and MEK inhibitors that have demonstrated improved patient outcomes include dabrafenib with trametinib, vemurafenib with cobimetinib or encorafenib with binimetinib. Treatment with BRAF and MEK inhibitors has met challenges as patient responses began to drop due to the development of resistance to these inhibitors which paved the way for development of immunotherapies and other small molecule inhibitor approaches to address this. Resistance to these inhibitors continues to push the need to expand our understanding of novel mechanisms of resistance associated with treatment therapies. This review focuses on the current landscape of how resistance occurs with the chronic use of BRAF and MEK inhibitors in BRAF-mutant melanoma and progress made in the fields of immunotherapies and other small molecules when used alone or in combination with BRAF and MEK inhibitors to delay or circumvent the onset of resistance for patients with stage III/IV BRAF mutant melanoma.

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Section: Axl Inhibitorsmentioning

confidence: 99%

Current Advances in the Treatment of BRAF-Mutant Melanoma

Patel

Yacoub

Mishra

et al. 2020

Cancers

125

102

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“…Although the mechanisms involved are not fully understood, the roles of AXL and MER in cancer are governed essentially by deregulation of transcription leading, directly or indirectly, to increased levels of the activated proteins [ 1 ••, 2 , 10 ]. In the few cases where chromosome amplifications, mutations or gene fusions have been described, functional evidence is lacking [ 11 – 14 ].…”

Section: Regulation Of Axl and Mer Expressionmentioning

confidence: 99%

Key Roles of AXL and MER Receptor Tyrosine Kinases in Resistance to Multiple Anticancer Therapies

Schoumacher¹,

Burbridge

2017

Curr Oncol Rep

105

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A major challenge in anticancer treatment is the pre-existence or emergence of resistance to therapy. AXL and MER are two members of the TAM (TYRO3-AXL-MER) family of receptor tyrosine kinases, which, when activated, can regulate tumor cell survival, proliferation, migration and invasion, angiogenesis, and tumor-host interactions. An increasing body of evidence strongly suggests that these receptors play major roles in resistance to targeted therapies and conventional cytotoxic agents. Multiple resistance mechanisms exist, including the direct and indirect crosstalk of AXL and MER with other receptors and the activation of feedback loops regulating AXL and MER expression and activity. These mechanisms may be innate, adaptive, or acquired. A principal role of AXL appears to be in sustaining a mesenchymal phenotype, itself a major mechanism of resistance to diverse anticancer therapies. Both AXL and MER play a role in the repression of the innate immune response which may also limit response to treatment. Small molecule and antibody inhibitors of AXL and MER have recently been described, and some of these have already entered clinical trials. The optimal design of treatment strategies to maximize the clinical benefit of these AXL and MER targeting agents are discussed in relation to the different cancer types and the types of resistance encountered. One of the major challenges to successful development of these therapies will be the application of robust predictive biomarkers for clear-cut patient stratification.

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“…4B). Recently, aberrant AXL was reported to be associated with tumor invasion by inducing MMPs or uPA or triggering EMT signaling (19,31). As a result, MMP1, 2, 3, 9, 12 and uPA, and the EMT-associated molecules, such as twist1, slug, snail, E-cadherin and N-cadherin were examined to evaluate the molecular contribution of XBP1 in OSCC invasion through AXL signaling.…”

Section: Inhibition Of Xbp1 Suppresses Cell Invasion In Vitromentioning

confidence: 99%

XBP1 promotes tumor invasion and is associated with poor prognosis in oral squamous cell carcinoma

et al. 2018

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X‑box‑binding protein 1 (XBP1) contributes to various types of cancer including breast, bladder cancer and esophageal squamous cell carcinoma. The aim of the study was to examine the metastatic role of XBP1 in oral squamous cell carcinoma (OSCC), and identify possible downstream molecules. Immunohistochemical staining was conducted on tissue microarrays comprising 96 OSCC cases to determine the expression level of XBP1 and analyze its association with metastasis, clinicopathological characteristics and survival prognosis. Compared with the adjacent normal tissues of OSCC, the expression of XBP1 was significantly increased in the tumor center and front area, and lymph nodes metastases (P<0.05). A relatively high XBP1 expression was associated with histological grades (P<0.05), advanced clinical stages (P<0.05), unfavorable 5‑year survival (P=0.027). Suppressed XBP1 expression caused a significant reduction of cell invasion capability (P<0.05). AXL and the downstream molecules, such as PI3K, MMP1, MMP3, and uPA were significantly suppressed when XBP1 expression was inhibited in OSCC cells. Once XBP1 was activated by Thapsigargin, AXL expression was restored. Moreover, aberrant AXL expression was associated with XBP1 overexpression in OSCC tissues (P<0.05). In conclusion, XBP1 is a potential target that is relevant to suppressing cell invasion and is associated with patient prognosis in OSCC.

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Role of the Receptor Tyrosine Kinase Axl and its Targeting in Cancer Cells

Cited by 37 publications

References 103 publications

Current Advances in the Treatment of BRAF-Mutant Melanoma

Current Advances in the Treatment of BRAF-Mutant Melanoma

Key Roles of AXL and MER Receptor Tyrosine Kinases in Resistance to Multiple Anticancer Therapies

XBP1 promotes tumor invasion and is associated with poor prognosis in oral squamous cell carcinoma

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