MERTK in cancer therapy: Targeting the receptor tyrosine kinase in tumor cells and the immune system

Huelse, Justus M.; Fridlyand, Diana; Earp, Shelton; DeRyckere, Deborah; Graham, Douglas K.

doi:10.1016/j.pharmthera.2020.107577

Cited by 59 publications

(58 citation statements)

References 303 publications

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“…Accompanying this were significant changes in regulators of inflammation that were consistent with a shift from AXL to MERTK signaling, which have been distinguished in carefully controlled studies [43] that refine our understanding of TAM receptor signaling in tumor immune surveillance [51,52]. Indeed, recent studies show that MERTK signaling contributes to an immunosuppressive environment by inducing an anti-inflammatory cytokine profile and regulating checkpoint inhibitor signaling in hematopoietic and solid tumors [53][54][55]. Our xenograft studies in immunocompromised SCID/Beige mice would be unlikely to display these changes as a pro-tumorigenic transition from J82 to MDXC1.…”

Section: Plos Onementioning

confidence: 84%

Autocrine signaling by receptor tyrosine kinases in urothelial carcinoma of the bladder

Lee

Silva

et al. 2021

PLoS ONE

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Comprehensive characterizations of bladder cancer (BCa) have established molecular phenotype classes with distinct alterations and survival trends. Extending these studies within the tyrosine kinase (TK) family to identify disease drivers could improve our use of TK inhibitors to treat specific patient groups or individuals. We examined the expression distribution of TKs as a class (n = 89) in The Cancer Genome Atlas (TCGA) muscle invasive BCa data set (n >400). Patient profiles of potentially oncogenic alterations (overexpression and/or amplification) clustered TKs into 3 groups; alterations of group 1 and 3 TKs were associated with significantly worse patient survival relative to those without alterations. Many TK pathways induce epithelial-to-mesenchymal transition (EMT), which promotes tumor invasiveness and metastasis. Overexpression and/or amplification among 9 EMT transcriptional activators occurred in 43% of TCGA cases. Co-occurring alterations of TKs and EMT transcriptional activators involved most group 1 TKs; 24% of these events were associated with significantly worse patient survival. Co-occurring alterations of receptor TKs and their cognate ligands occurred in 16% of TCGA cases and several BCa-derived cell lines. Suppression of GAS6, MST1 or CSF1, or their respective receptors (AXL, MST1R and CSF1R), in BCa cell lines was associated with decreased receptor activation, cell migration, cell proliferation and anchorage independent cell growth. These studies reveal the patterns and prevalence of potentially oncogenic TK pathway-related alterations in BCa and identify specific alterations associated with reduced BCa patient survival. Detection of these features in BCa patients could better inform TK inhibitor use and improve clinical outcomes.

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Section: Plos Onementioning

confidence: 84%

Autocrine signaling by receptor tyrosine kinases in urothelial carcinoma of the bladder

Lee

Silva

et al. 2021

PLoS ONE

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“…MerTK blockade in mouse models of cancer resulted in the accumulation of apoptotic tumor cells, leading to subsequent cyclic cGAS/STING activation and IFN I‐driven anti‐tumor immune responses 160 . Because MerTK signaling is a known inducer of tumor‐supportive and immune modulatory macrophages, 161 targeting this axis may ensure TME reprogramming via complementary mechanisms.…”

Section: Emerging Approaches For Therapeutic Tam Reprogrammingmentioning

confidence: 99%

Determinants, mechanisms, and functional outcomes of myeloid cell diversity in cancer

Caronni

Montaldo

Mezzanzanica

et al. 2021

Immunological Reviews

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The tumor microenvironment (TME) is a complex architecture of cells, including those of the immune system, of matrix components, and of their interactions within the unique physical traits of the cancer tissue. 1,2 Many elements influence the composition and cellular dynamics of the TME, such as the anatomical site, the type, and stage of the disease, the therapeutic regimen as well as host factors like age, sex, and comorbidities. 2 Within the extreme diversity of TMEs, parameters integrating the relative composition, spatial arrangement, and functional properties of infiltrating immune cells are useful indicators of disease progression and response to therapies. 2,3 For instance, high tumor infiltration of cytotoxic CD8 + T cells engaging inhibitory crosstalk in the TME via the programmed death (PD)1:PD-L1/PD-L2 axis often predicts efficient response to immune checkpoint blockade therapy. 3 In some cases, CD8 + T cells form organized assemblies with antigen-presenting cells such as dendritic cells (DCs), B cells, and macrophages within the tumor stroma; these so-called tertiary lymphoid structures are considered sites of efficient T-cell priming, and their presence is associated with good response to immunotherapy. 4 In this context, a subset of conventional DCs, termed cDC1, can efficiently cross-present tumor antigens for the induction of a durable immune response. 5-7 Accumulation of cDC1 at the tumor site is mediated at least in part by chemokines released by infiltrating natural killer (NK) cells, 8 a

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“…Tyrosine kinase-targeted therapies (TKi) have revolutionized the treatment of many cancers in the last years (1,2). These drugs used alone or combined to other anticancer drugs have improved antitumor efficacy and have fewer toxic side-effects, compared to traditional chemotherapy, however, many adverse cardiac events have been recorded, including QT prolongation, heart failure and cardiac fibrosis (3,4).…”

Section: Introductionmentioning

confidence: 99%

Polydatin Reduces Cardiotoxicity and Enhances the Anticancer Effects of Sunitinib by Decreasing Pro-Oxidative Stress, Pro-Inflammatory Cytokines, and NLRP3 Inflammasome Expression

et al. 2021

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Renal cell carcinoma (RCC) represents the main renal tumors and are highly metastatic. Sunitinib, a recently-approved, multi-targeted Tyrosine Kinases Inhibitor (TKi), prolongs survival in patients with metastatic renal cell carcinoma and gastrointestinal stromal tumors, however a dose related cardiotoxicity was well described. Polydatin (3,4’,5-trihydroxystilbene-3-β-d-glucoside) is a monocrystalline compound isolated from Polygonum cuspidatum with consolidated anti-oxidant and anti-inflammatory properties, however no studies investigated on its putative cardioprotective and chemosensitizing properties during incubation with sunitinib. We investigated on the effects of polydatin on the oxidative stress, NLRP3 inflammasome and Myd88 expression, highlighting on the production of cytokines and chemokines (IL-1β, IL-6, IL-8, CXCL-12 and TGF-β) during treatment with sunitinib. Exposure of cardiomyocytes and cardiomyoblasts (AC-16 and H9C2 cell lines) and human renal adenocarcinoma cells (769‐P and A498) to polydatin combined to plasma-relevant concentrations of sunitinib reduces significantly iROS, MDA and LTB4 compared to only sunitinib-treated cells (P<0.001). In renal cancer cells and cardiomyocytes polydatin reduces expression of pro-inflammatory cytokines and chemokines involved in myocardial damages and chemoresistance and down-regulates the signaling pathway of NLRP3 inflammasome, MyD88 and NF-κB. Data of the present study, although in vitro, indicate that polydatin, besides reducing oxidative stress, reduces key chemokines involved in cancer cell survival, chemoresistance and cardiac damages of sunitinib through downregulation of NLRP3-MyD88 pathway, applying as a potential nutraceutical agent in preclinical studies of preventive cardio-oncology.

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MERTK in cancer therapy: Targeting the receptor tyrosine kinase in tumor cells and the immune system

Cited by 59 publications

References 303 publications

Autocrine signaling by receptor tyrosine kinases in urothelial carcinoma of the bladder

Autocrine signaling by receptor tyrosine kinases in urothelial carcinoma of the bladder

Determinants, mechanisms, and functional outcomes of myeloid cell diversity in cancer

Polydatin Reduces Cardiotoxicity and Enhances the Anticancer Effects of Sunitinib by Decreasing Pro-Oxidative Stress, Pro-Inflammatory Cytokines, and NLRP3 Inflammasome Expression

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