AXL Receptor in Cancer Metastasis and Drug Resistance: When Normal Functions Go Askew

Auyez, Almira; Sayan, Emre; Kriajevska, Marina; Tulchinsky, Eugene

doi:10.3390/cancers13194864

Cited by 31 publications

(27 citation statements)

References 128 publications

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“…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

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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).

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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

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“…The overexpression of TGF-β in tumor cells exerts dual effects: regulating the expression of PD-L1 and VEGF and affecting biomarkers associated with the modulation of immune response and evasion, including Foxp3/Treg, MDSC, Th1/Th2 balance, and macrophage cells [ 9 , 10 , 17 , 18 , 19 , 49 , 56 , 57 , 58 ]. HIFs and TGF-β are biomarkers associated with the expression of the AXL gene, which is highly overexpressed in tumors with a loss of VHL function and is associated with a poor response to biologically targeted molecules [ 59 , 60 , 61 , 62 , 63 ]. Based on published data generated by others and data generated in our laboratory, Figure 4 is presented to illustrate the potential role of miR-210, miR-155, TGF-β, and HIFs individually or collectively in the regulation of multiple targets.…”

Section: Discussionmentioning

confidence: 99%

MicroRNA Expression in Clear Cell Renal Cell Carcinoma Cell Lines and Tumor Biopsies: Potential Therapeutic Targets

Swearson

Rataan

Eliason

et al. 2022

IJMS

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This study was carried out to quantitate the expression levels of microRNA-17, -19a, -34a, -155, and -210 (miRs) expressed in nine clear cell renal cell carcinoma (ccRCC) and one chromophobe renal cell carcinoma cell line with and without sarcomatoid differentiation, and in six primary kidney tumors with matching normal kidney tissues. The data in the five non-sarcomatoid ccRCC cell lines—RC2, CAKI-1, 786-0, RCC4, and RCC4/VHL—and in the four ccRCC with sarcomatoid differentiation—RCJ41T1, RCJ41T2, RCJ41M, and UOK-127—indicated that miR-17 and -19a were expressed at lower levels relative to miR-34a, -155, and -210. Compared with RPTEC normal epithelial cells, miR-34a, miR-155, and miR-210 were expressed at higher levels, independent of the sarcomatoid differentiation status and hypoxia-inducible factors 1α and 2α (HIFs) isoform expression. In the one chromophobe renal cell carcinoma cell line, namely, UOK-276 with sarcomatoid differentiation, and expressing tumor suppressor gene TP53, miR-34a, which is a tumor suppressor gene, was expressed at higher levels than miR-210, -155, -17, and -19a. The pilot results generated in six tumor biopsies with matching normal kidney tissues indicated that while the expression of miR-17 and -19a were similar to the normal tissue expression profile, miR-210, -155, -and 34a were expressed at a higher level. To confirm that differences in the expression levels of the five miRs in the six tumor biopsies were statistically significant, the acquisition of a larger sample size is required. Data previously generated in ccRCC cell lines demonstrating that miR-210, miR-155, and HIFs are druggable targets using a defined dose and schedule of selenium-containing molecules support the concept that simultaneous and concurrent downregulation of miR-210, miR-155, and HIFs, which regulate target genes associated with increased tumor angiogenesis and drug resistance, may offer the potential for the development of a novel mechanism-based strategy for the treatment of patients with advanced ccRCC.

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“…Taken together, AXL contribute to epithelial plasticity programs in mammary stem and progenitor cells, and, when co-opted, maintains acquired stemness in BCa cells. It is well documented that AXL is particularly important for persister cells ( 119 ). Shaffer and colleagues demonstrated that human melanoma cells exhibit profound transcriptional variability at the single-cell level.…”

Section: Axl and Epithelial-mesenchymal Plasticitymentioning

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

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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.

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AXL Receptor in Cancer Metastasis and Drug Resistance: When Normal Functions Go Askew

Cited by 31 publications

References 128 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

MicroRNA Expression in Clear Cell Renal Cell Carcinoma Cell Lines and Tumor Biopsies: Potential Therapeutic Targets

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

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