Explore the vast range of titles available.

The E3 ligase Cbl-b acts on TAM tyrosine kinase receptors and has a critical role in the regulation of natural killer (NK) cell rejection of metastatic tumours; a small molecule TAM kinase inhibitor is shown to enhance the anti-metastatic NK cell activity. Controlling NK cell anti-metastatic activity This study describes a previously unknown role for the E3 ubiquitin ligase Cbl-b as part of a regulatory pathway in innate natural killer (NK) cells that licenses them to spontaneously reject cancer metastases. Genetic loss of Cbl-b or inactivation of its E3 ligase activity in mice allows NK cells to suppress growth of both multiple primary tumours and distant tumour metastases. The effect is mediated via members of the TAM family tyrosine kinase receptors, and treatment of wild-type NK cells with a small-molecule TAM inhibitor conferred therapeutic NK cell activity against metastatic melanomas. This suggests a possible approach for NK-cell-based anti-metastatic therapy in humans and at the same time explains the anti-metastatic properties of the widely used anticoagulant warfarin. Tumour metastasis is the primary cause of mortality in cancer patients and remains the key challenge for cancer therapy 1 . New therapeutic approaches to block inhibitory pathways of the immune system have renewed hopes for the utility of such therapies 2 . Here we show that genetic deletion of the E3 ubiquitin ligase Cbl-b (casitas B-lineage lymphoma-b) or targeted inactivation of its E3 ligase activity licenses natural killer (NK) cells to spontaneously reject metastatic tumours. The TAM tyrosine kinase receptors Tyro3, Axl and Mer (also known as Mertk) were identified as ubiquitylation substrates for Cbl-b. Treatment of wild-type NK cells with a newly developed small molecule TAM kinase inhibitor conferred therapeutic potential, efficiently enhancing anti-metastatic NK cell activity in vivo . Oral or intraperitoneal administration using this TAM inhibitor markedly reduced murine mammary cancer and melanoma metastases dependent on NK cells. We further report that the anticoagulant warfarin exerts anti-metastatic activity in mice via Cbl-b/TAM receptors in NK cells, providing a molecular explanation for a 50-year-old puzzle in cancer biology 3 . This novel TAM/Cbl-b inhibitory pathway shows that it might be possible to develop a ‘pill’ that awakens the innate immune system to kill cancer metastases.

Background Overexpression of AXL receptor tyrosine kinase (AXL) in various human cancers correlates with reduced patients overall survival and resistance to first line therapies. Therefore, several AXL tyrosine kinase inhibitors (TKIs) are currently under clinical evaluation. Results AXL TKI BMS777607 treatment increased AXL protein levels after 24 h as observed by Western blot and flow cytometry analysis. Mechanistically, this inhibition-induced AXL cell surface accumulation was neither associated with epigenetic modifications, nor altered transcriptional and translational regulation. Further, we saw no impact on glycosylation and receptor shedding by α-secretases. However, we observed that BMS777607 increased the glycosylated 140 kDa AXL protein abundance, which was impaired in the kinase dead mutant AXL (K567R). We demonstrated that AXL kinase activity and subsequent kinase phosphorylation is necessary for GAS6-dependent receptor internalization and degradation. Blocking of kinase function by BMS777607 resulted in ubiquitination prohibition, impaired internalization and subsequent cell surface accumulation. Subsequently, AXL cell surface accumulation was accompanied by increased proliferation of 3D-Speroids induced by low μM levels of BMS777607 treatment. Conclusion Our data suggest a re-evaluation of anti-AXL clinical protocols due to possible feedback loops and resistance formation to targeted AXL therapy. An alternative strategy to circumvent feedback loops for AXL targeting therapies may exist in linkage of AXL TKIs to a degradation machinery recruiting unit, as already demonstrated with PROTACs for EGFR, HER2, and c-Met. This might result in a sustained inhibition and depletion of the AXL from tumor cell surface and enhance the efficacy of targeted anti-AXL therapies in the clinic.

AXL receptor tyrosine kinase (RTK) inhibition presents a promising therapeutic strategy for aggressive tumor subtypes, as AXL signaling is upregulated in many cancers resistant to first‐line treatments. Furthermore, the AXL ligand growth arrest‐specific gene 6 (GAS6) has recently been linked to cancer drug resistance. Here, we established that challenging conditions, such as serum deprivation, divide AXL‐overexpressing tumor cell lines into non‐self‐sustaining and self‐sustaining subtypes in 3D spheroid culture. Self‐sustaining cells are characterized by excessive GAS6 secretion and TAM‐PDK‐RSK‐mTOR pathway activation. In 3D spheroid culture, the activation of the TAM‐PDK‐RSK‐mTOR pathway proves crucial following treatment with AXL/MET inhibitor BMS777607, when the self‐sustaining tumor cells react with TAM‐RSK hyperactivation and enhanced SRC‐AKT‐mTOR signaling. Thus, bidirectional activated mTOR leads to enhanced proliferation and counteracts the drug effect. mTOR activation is accompanied by an enhanced AXL expression and hyperphosphorylation following 24 h of treatment with BMS777607. Therefore, we elucidate a double role of AXL that can be assigned to RSK‐mTOR as well as SRC‐AKT‐mTOR pathway activation, specifically through AXL Y779 phosphorylation. This phosphosite fuels the resistance mechanism in 3D spheroids, alongside further SRC‐dependent EGFR Y1173 and/or MET Y1349 phosphorylation which is defined by the cell‐specific addiction. In conclusion, self‐sustenance in cancer cells is based on a signaling synergy, individually balanced between GAS6 TAM‐dependent PDK‐RSK‐mTOR survival pathway and the AXLY779/EGFR/MET‐driven SRC‐mTOR pathway. AXL inhibition presents a promising therapeutic strategy for aggressive tumor subtypes. In 3D spheroids, the activation of the TAM‐PDK‐RSK‐mTOR pathway proves crucial following treatment with BMS777607, when the self‐sustaining tumor cells react with TAM‐RSK hyperactivation and enhanced SRC‐AKT‐mTOR signaling. Self‐sustenance in cancer cells is based on signaling synergy, individually balanced between GAS6‐TAM‐dependent PDK‐RSK‐mTOR survival pathway and the AXLY779/EGFR/MET‐driven SRC‐mTOR pathway.

AXL receptor tyrosine kinase ( RTK ) inhibition presents a promising therapeutic strategy for aggressive tumor subtypes, as AXL signaling is upregulated in many cancers resistant to first‐line treatments. Furthermore, the AXL ligand growth arrest‐specific gene 6 ( GAS 6) has recently been linked to cancer drug resistance. Here, we established that challenging conditions, such as serum deprivation, divide AXL ‐overexpressing tumor cell lines into non‐self‐sustaining and self‐sustaining subtypes in 3D spheroid culture. Self‐sustaining cells are characterized by excessive GAS 6 secretion and TAM ‐ PDK ‐ RSK ‐ mTOR pathway activation. In 3D spheroid culture, the activation of the TAM ‐ PDK ‐ RSK ‐ mTOR pathway proves crucial following treatment with AXL / MET inhibitor BMS 777607, when the self‐sustaining tumor cells react with TAM ‐ RSK hyperactivation and enhanced SRC ‐ AKT ‐ mTOR signaling. Thus, bidirectional activated mTOR leads to enhanced proliferation and counteracts the drug effect. mTOR activation is accompanied by an enhanced AXL expression and hyperphosphorylation following 24 h of treatment with BMS 777607. Therefore, we elucidate a double role of AXL that can be assigned to RSK ‐ mTOR as well as SRC ‐ AKT ‐ mTOR pathway activation, specifically through AXL Y779 phosphorylation. This phosphosite fuels the resistance mechanism in 3D spheroids, alongside further SRC ‐dependent EGFR Y1173 and/or MET Y1349 phosphorylation which is defined by the cell‐specific addiction. In conclusion, self‐sustenance in cancer cells is based on a signaling synergy, individually balanced between GAS 6 TAM ‐dependent PDK ‐ RSK ‐ mTOR survival pathway and the AXLY 779/ EGFR / MET ‐driven SRC ‐ mTOR pathway.

In a large, multinational, randomized trial, continuous lenalidomide maintenance therapy after triplet therapy (lenalidomide, bortezomib, and dexamethasone) and autologous stem-cell transplantation resulted in longer progression-free survival than triplet therapy alone.

Background Patients with mantle cell lymphoma (MCL) exhibit a wide variation in clinical presentation and outcome. However, the commonly used prognostic models are outdated and inadequate to address the needs of the current multidisciplinary management of this disease. This study aims to investigate the clinical and pathological features of MCL in the immunochemotherapy era and improve the prognostic models for a more accurate prediction of patient outcomes. Methods The North American Mantle Cell Lymphoma Project is a multi-institutional collaboration of 23 institutions across North America to evaluate and refine prognosticators for front-line therapy. A total of 586 MCL cases diagnosed between 2000 and 2012 are included in this study. A comprehensive retrospective analysis was performed on the clinicopathological features, treatment approaches, and outcomes of these cases. The establishment of novel prognostic models was based on in-depth examination of baseline parameters, and subsequent validation in an independent cohort of MCL cases. Results In front-line strategies, the use of hematopoietic stem cell transplantation was the most significant parameter affecting outcomes, for both overall survival (OS, p  < 0.0001) and progression-free survival (PFS, p  < 0.0001). P53 positive expression was the most significant pathological parameter correlating with inferior outcomes ( p  < 0.0001 for OS and p  = 0.0021 for PFS). Based on the baseline risk factor profile, we developed a set of prognostic models incorporating clinical, laboratory, and pathological parameters that are specifically tailored for various applications. These models, when tested in the validation cohort, exhibited strong predictive power for survival and showed a stratification resembling the training cohort. Conclusions The outcome of patients with MCL has markedly improved over the past two decades, and further enhancement is anticipated with the evolution of clinical management. The innovative prognostic models developed in this study would serve as a valuable tool to guide the selection of more suitable treatment strategies for patients with MCL.