Targeting MERTK and AXL in EGFR Mutant Non-Small Cell Lung Cancer

Yan, Dan; Earp, H. Shelton; DeRyckere, Deborah; Graham, Douglas K.

doi:10.3390/cancers13225639

Cited by 16 publications

(10 citation statements)

References 280 publications

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“…Similarly, GAS6 and PROS1 were significantly increased, and there was a trend toward increased MERTK expression in tumor biopsies from patients with EGFR MT NSCLC after treatment with OSI. While GAS6 can activate both MERTK and AXL, AXL is not activated by PROS1 ( 45 ). Thus, these data are consistent with induction of autocrine-mediated MERTK signaling in both murine xenografts and patients treated with OSI.…”

Section: Discussionmentioning

confidence: 99%

MERTK activation drives osimertinib resistance in EGFR-mutant non–small cell lung cancer

Yan¹,

Huelse²,

Kireev³

et al. 2022

Journal of Clinical Investigation

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Acquired resistance is inevitable in non–small cell lung cancers (NSCLCs) treated with osimertinib (OSI), and the mechanisms are not well defined. The MERTK ligand GAS6 promoted downstream oncogenic signaling in EGFR -mutated ( EGFR MT ) NSCLC cells treated with OSI, suggesting a role for MERTK activation in OSI resistance. Indeed, treatment with MRX-2843, a first-in-class MERTK kinase inhibitor, resensitized GAS6-treated NSCLC cells to OSI. Both GAS6 and EGF stimulated downstream PI3K/AKT and MAPK/ERK signaling in parental cells, but only GAS6 activated these pathways in OSI-resistant (OSIR) derivative cell lines. Functionally, OSIR cells were more sensitive to MRX-2843 than parental cells, suggesting acquired dependence on MERTK signaling. Furthermore, MERTK and/or its ligands were dramatically upregulated in EGFR MT tumors after treatment with OSI in both xenograft models and patient samples, consistent with induction of autocrine/paracrine MERTK activation. Moreover, treatment with MRX-2843 in combination with OSI, but not OSI alone, provided durable suppression of tumor growth in vivo, even after treatment was stopped. These data identify MERTK as a driver of bypass signaling in treatment-naive and EGFR MT -OSIR NSCLC cells and predict that MRX-2843 and OSI combination therapy will provide clinical benefit in patients with EGFR MT NSCLC.

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Section: Discussionmentioning

confidence: 99%

MERTK activation drives osimertinib resistance in EGFR-mutant non–small cell lung cancer

Yan¹,

Huelse²,

Kireev³

et al. 2022

Journal of Clinical Investigation

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“…TAM receptors are expressed by various cell types and activated by vitamin K-dependent ligands, growth arrest-specific factor 6 (GAS6), and protein S (PROS1), representing the two best-characterized TAM ligands. TYRO3, AXL, and MERTK exert multiple functions, and despite the partial overlap, the three TAM receptors display different expression patterns ( 8 , 9 , 21 , 22 ). The TAM receptors also exhibit distinct activation patterns.…”

Section: The Biology Of Tams and Gas6/axl Signalingmentioning

confidence: 99%

“…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%

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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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“…There were 828 100 newly diagnosed lung cancer cases in 2016 in China 2 . Non‐small cell lung carcinoma (NSCLC) accounts for approximately 85% of all lung cancers with limited clinical treatment 3 . The EGF receptor tyrosine kinase inhibitor (EGFR‐TKI) gefitinib has exhibited good initial efficacy in NSCLC patients.…”

Section: Introductionmentioning

confidence: 99%

FBP1 induced by β‐elemene enhances the sensitivity of gefitinib in lung cancer

Dai

Sun

et al. 2022

Thoracic Cancer

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Background: β-elemene is known to play a critical role in tumorigenesis as well as tyrosine kinase inhibitor (TKI) resistance in lung cancer. However, the biological function and molecular mechanism remain largely unknown. Methods: In this study, the common genes involved in gefitinib resistance and β-elemene were identified using bioinformatic analysis. The expression of FBP1 was examined by qRT-PCR and Western blot analysis. Cell proliferation, flow cytometry, clone formation and IC50 assays were performed to assess the effects of β-elemene and FBP1. Western blot analysis was used to evaluate apoptosis-related gene expression. Finally, in vivo experiments were conducted to assess the crucial role of FBP1 in gefitinib-resistant HCC827/GR cells in nude mice. Results: Screening analysis demonstrated that fructose-1,6-bisphosphatase (FBP1) was induced by β-elemene and downregulated in gefitinib-resistant lung cells. Functionally, overexpression of FBP1 inhibited proliferation and gefitinib resistance and promoted apoptosis of PC9/GR and HCC827/GR cells in vitro. Mechanistically, FBP1 impeded the nuclear translocation of p-STAT3. The FBP1/STAT3 axis was required for FBP1-mediated apoptosis-related gene expression. In vivo experiments further confirmed the enhanced effects of FBP1 on lung cancer cell sensitivity to gefitinib. Conclusion: Our research indicated that β-elemene suppressed proliferation and enhanced sensitivity to gefitinib by inducing apoptosis through the FBP1/STAT3 axis in gefitinib-resistant lung cancer cells.

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Targeting MERTK and AXL in EGFR Mutant Non-Small Cell Lung Cancer

Cited by 16 publications

References 280 publications

MERTK activation drives osimertinib resistance in EGFR-mutant non–small cell lung cancer

MERTK activation drives osimertinib resistance in EGFR-mutant non–small cell lung cancer

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

FBP1 induced by β‐elemene enhances the sensitivity of gefitinib in lung cancer

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