Therapeutic Targeting of the Gas6/Axl Signaling Pathway in Cancer

Tanaka, Mai; Siemann, Dietmar W.

doi:10.3390/ijms22189953

Cited by 39 publications

(34 citation statements)

References 166 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…It was observed that Gas6 is frequently overexpressed in lung cancer cells and is found in the plasma [ 42 , 43 ], and Gas6 is associated with cell growth of stromal cancerous cells and tumor progression [ 44 ]. Therapeutic agents targeting Gas6 and AXL have been developed, and promising results have been observed in both preclinical and clinical settings when such agents are used alone or in combination [ 45 ].…”

Section: Discussionmentioning

confidence: 99%

The First Evaluation of Serum Levels of MGP, Gas6 and EGFR after First Dose of Chemotherapy in Lung Cancer

Crintea

Duţu

Constantin

et al. 2022

Biology

View full text Add to dashboard Cite

Background: Vitamin K-dependent proteins (VKDPs) and the epidermal growth factor receptor (EGFR) are involved in lung cancer progression. Therefore, we aimed to study the serum concentration of Matrix Gla protein (MGP), Growth Arrest-specific 6 (Gas6), and EGFR before and after the first cycle of chemotherapy and to investigate how MGP, Gas6, and EGFR are modified after one cycle of chemotherapy. Methods: We performed an observational study on twenty patients diagnosed with lung cancer, by assessing the serum concentration of vitaminK1 (VitK1), MGP, Gas6, and EGFR using the ELISA technique before and after three weeks of the first cycle of chemotherapy. Patients were evaluated using RECIST 1.1 criteria. Results: Serum levels of MGP, Gas6, EGFR, and VK1 before and after treatment were not changed significantly. Regarding the pre-treatment correlation of the MGP values, we found a strong positive relationship between MGP and VK1 pre-treatment values (r = 0.821, 95%CI 0.523; 0.954, p < 0.001). Furthermore, there was a moderately negative correlation between VK1 and EGFR pre-treatment values, with the relationship between them being marginally significant (r = −0.430, 95%CI −0.772; 0.001, p = 0.058). Post-treatment, we found a strong positive relationship between MGP and VK1 post-treatment values (r = 0.758, 95%CI 0.436; 0.900, p < 0.001). We also found a moderate positive relationship between Gas6 and EGFR post-treatment values, but the correlation was only marginally significant (r = 0.442, p = 0.051).

show abstract

Section: Discussionmentioning

confidence: 99%

The First Evaluation of Serum Levels of MGP, Gas6 and EGFR after First Dose of Chemotherapy in Lung Cancer

Crintea

Duţu

Constantin

et al. 2022

Biology

View full text Add to dashboard Cite

show abstract

“…Important tyrosine residues in the intracellular domain include the activation loop (Tyr698, Tyr702, Tyr703) and the C-terminal domain (Tyr779, Tyr821, Tyr866), which are necessary for the recruitment of adaptor proteins mediating signaling cascades including the adaptor GRB2 leading to the activation of phosphatidylinositol 3 kinase (PI3K), phospholipase C (PLC), or SRC kinase. In a cell type- and tissue-dependent context, it triggers the downstream activation of various signaling pathways, including PI3K-AKT, NF-KappaB; RAS-MEK-ERK, JAK-STAT, SRC/FAK ( 6 , 7 , 21 , 22 , 36 – 38 ). In addition to the canonical GAS6/AXL activation pathway, evidence is accumulating that malignant cells have developed various ways to bypass, at least in part, their dependence on GAS6 ( 21 , 39 – 41 ).…”

Section: The Biology Of Tams and Gas6/axl Signalingmentioning

confidence: 99%

“…Due to the pro-tumoral, pro-metastatic, and treatment resistance roles of AXL, numerous therapeutic interventions targeting AXL have been designed and investigated. Several investigators have covered this topic well to which the readers can be referred ( 7 , 21 , 22 , 30 , 36 – 38 , 53 , 119 , 172 , 195 ).…”

Section: Toward Standardization Of Axl-targeting Agents In Combinatio...mentioning

confidence: 99%

Dissecting the Role of AXL in Cancer Immune Escape and Resistance to Immune Checkpoint Inhibition

et al. 2022

View full text Add to dashboard Cite

The development and implementation of Immune Checkpoint Inhibitors (ICI) in clinical oncology have significantly improved the survival of a subset of cancer patients with metastatic disease previously considered uniformly lethal. However, the low response rates and the low number of patients with durable clinical responses remain major concerns and underscore the limited understanding of mechanisms regulating anti-tumor immunity and tumor immune resistance. There is an urgent unmet need for novel approaches to enhance the efficacy of ICI in the clinic, and for predictive tools that can accurately predict ICI responders based on the composition of their tumor microenvironment. The receptor tyrosine kinase (RTK) AXL has been associated with poor prognosis in numerous malignancies and the emergence of therapy resistance. AXL is a member of the TYRO3-AXL-MERTK (TAM) kinase family. Upon binding to its ligand GAS6, AXL regulates cell signaling cascades and cellular communication between various components of the tumor microenvironment, including cancer cells, endothelial cells, and immune cells. Converging evidence points to AXL as an attractive molecular target to overcome therapy resistance and immunosuppression, supported by the potential of AXL inhibitors to improve ICI efficacy. Here, we review the current literature on the prominent role of AXL in regulating cancer progression, with particular attention to its effects on anti-tumor immune response and resistance to ICI. We discuss future directions with the aim to understand better the complex role of AXL and TAM receptors in cancer and the potential value of this knowledge and targeted inhibition for the benefit of cancer patients.

show abstract

“…Among the three receptors, Axl has the highest affinity for GAS6 (Tanaka & Siemann, 2021). Multiple studies focused on GAS6/Axl signaling in the progression and metastasis of cancer (Tanaka & Siemann, 2021). Furthermore, the role of the GAS6/Axl pathway in organ protection, especially brain, under various pathological progresses has also been widely investigated (Ray et al, 2017; Sun et al, 2021).…”

Section: Introductionmentioning

confidence: 99%

“…Growth arrest-specific gene 6 (GAS6), discovered in 1988, is a Vitamin K-dependent protein and participates in immune regulation and inflammation by binding to the TAM receptor (Tyro3, Axl, and Mer). Among the three receptors, Axl has the highest affinity for GAS6 (Tanaka & Siemann, 2021). Multiple studies focused on GAS6/Axl signaling in the progression and metastasis of cancer (Tanaka & Siemann, 2021).…”

mentioning

confidence: 99%

Psoralidin protects against cerebral hypoxia/reoxygenation injury: Role of GAS6/Axl signaling

Lei

Zhao

et al. 2022

Phytotherapy Research

View full text Add to dashboard Cite

Psoralidin (PSO) is a natural phenolic coumarin extracted from the seeds of Psoralea corylifolia L. Growing preclinical evidence indicates that PSO has anti‐inflammatory, anti‐vitiligo, anti‐bacterial, and anti‐viral effects. Growth arrest‐specific gene 6 (GAS6) and its receptor, Axl, modulate cellular oxidative stress, apoptosis, survival, proliferation, migration, and mitogenesis. Notably, the neuroprotective role of the GAS6/Axl axis has been identified in previous studies. We hypothesize that PSO ameliorates cerebral hypoxia/reoxygenation (HR) injury via activating the GAS6/Axl signaling. We first confirmed that PSO was not toxic to the cells and upregulated GAS6 and Axl expression after HR injury. Moreover, PSO exerted a marked neuroprotective effect against HR injury, represented by restored cell viability and cell morphology, decreased lactate dehydrogenase (LDH) release, and reactive oxygen species (ROS) generation. Furthermore, PSO pretreatment also elevated the levels of nuclear factor‐related factor 2 (Nrf‐2), NAD(P)H dehydrogenase quinone‐1 (NQO1), heme oxygenase‐1 (HO‐1), silent information regulator 1 (SIRT1), peroxisome proliferator‐activated receptor coactivator 1α (PGC‐1α), nuclear respiratory factor 1 (NRF1), uncoupling protein 2 (UCP2), and B‐cell lymphoma 2 (BCl2) both in the condition of baseline and HR injury. However, GAS6 siRNA or Axl siRNA inhibited the neuroprotective effects of PSO. Our findings suggest that PSO pretreatment attenuated HR‐induced oxidative stress, apoptosis, and mitochondrial dysfunction in neuroblastoma cells through the activation of GAS6/Axl signaling.

show abstract

Therapeutic Targeting of the Gas6/Axl Signaling Pathway in Cancer

Cited by 39 publications

References 166 publications

The First Evaluation of Serum Levels of MGP, Gas6 and EGFR after First Dose of Chemotherapy in Lung Cancer

The First Evaluation of Serum Levels of MGP, Gas6 and EGFR after First Dose of Chemotherapy in Lung Cancer

Dissecting the Role of AXL in Cancer Immune Escape and Resistance to Immune Checkpoint Inhibition

Psoralidin protects against cerebral hypoxia/reoxygenation injury: Role of GAS6/Axl signaling

Contact Info

Product

Resources

About