Myosin II Reactivation and Cytoskeletal Remodeling as a Hallmark and a Vulnerability in Melanoma Therapy Resistance

Publication date: 13 January 2020Source: Cancer Cell, Volume 37, Issue 1Author(s): Jose L. Orgaz, Eva Crosas-Molist, Amine Sadok, Anna Perdrix-Rosell, Oscar Maiques, Irene Rodriguez-Hernandez, Jo Monger, Silvia Mele, Mirella Georgouli, Victoria Bridgeman, Panagiotis Karagiannis, Rebecca Lee, Pahini Pandya, Lena Boehme, Fredrik Wallberg, Chris Tape, Sophia N. Karagiannis, Ilaria Malanchi, Victoria Sanz-MorenoSummaryDespite substantial clinical benefit of targeted and immune checkpoint blockade-based therapies in melanoma, resistance inevitably develops. We show cytoskeletal remodeling and changes in expression and activity of ROCK-myosin II pathway during acquisition of resistance to MAPK inhibitors. MAPK regulates myosin II activity, but after initial therapy response, drug-resistant clones restore myosin II activity to increase survival. High ROCK-myosin II activity correlates with aggressiveness, identifying targeted therapy- and immunotherapy-resistant melanomas. Survival of resistant cells is myosin II dependent, regardless of the therapy. ROCK-myosin II ablation specifically kills resistant cells via intrinsic lethal reactive oxygen species and unresolved DNA damage and limits extrinsic myeloid and lymphoid immunosuppression. Efficacy of targeted therapies and immunotherapies can be improved by combination with ROCK inhibitors.Graphical Abstract
Source: Cancer Cell - Category: Cancer & Oncology Source Type: research

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Publication date: 18 February 2020Source: Cell Reports, Volume 30, Issue 7Author(s): Christopher E. Rudd, Kittiphat Chanthong, Alison TaylorSummaryImmune checkpoint blockade using antibodies against negative co-receptors such as cytolytic T cell antigen-4 (CTLA-4) and programmed cell death-1 (PD-1) has seen much success treating cancer. However, most patients are still not cured, underscoring the need for improved treatments and the possible development of small molecule inhibitors (SMIs) for improved immunotherapy. We previously showed that glycogen synthase kinase (GSK)-3α/β is a central regulator of PD-1...
Source: Cell Reports - Category: Cytology Source Type: research
anazi Garrett Melanoma is the most lethal form of skin cancer. Melanoma is usually curable with surgery if detected early, however, treatment options for patients with metastatic melanoma are limited and the five-year survival rate for metastatic melanoma had been 15–20% before the advent of immunotherapy. Treatment with immune checkpoint inhibitors has increased long-term survival outcomes in patients with advanced melanoma to as high as 50% although individual response can vary greatly. A mutation within the MAPK pathway leads to uncontrollable growth and ultimately develops into cancer. The most common ...
Source: Cancers - Category: Cancer & Oncology Authors: Tags: Review Source Type: research
This study aimed at investigating the value of applying positron emission tomography (PET) to early predict the effect of immune checkpoint inhibitors (ICIs) in malignant tumors.MethodsElectronic databases MEDLINE/PubMed, EMBASE, and Cochrane Library were searched to identify relevant trials. The primary endpoints were progression-free survival (PFS) and overall survival (OS). The results were analyzed utilizing SPSS 19.0 statistical software. Subgroup analyses were implemented based on primary  tumors, study designs, continents, type of ICIs, evaluation index of PET, and evaluated PET timing.ResultsFifteen studi...
Source: Cancer Immunology, Immunotherapy - Category: Cancer & Oncology Source Type: research
In their article, Baldini et al. evaluated the association between immune-related adverse events (irAEs) and clinical benefit among patients with non-small-cell lung cancer (NSCLC) treated with nivolumab in the Italian NSCLC expanded access program [1]. Accumulating evidence suggest that there is a correlation between irAEs incidence and therapeutic outcomes of immunotherapy. This has been widely demonstrated in several solid tumors, mostly in patients with melanoma [2] and NSCLC [3]. However, most retrospective reports in NSCLC mainly include patients of Asian ethnicity [4], and differences in treatment tolerability and o...
Source: Lung Cancer - Category: Cancer & Oncology Authors: Source Type: research
CONCLUSIONS: Our findings suggest that GNAQ/11 mutant non-uveal melanomas are a melanoma subtype distinct both clinically and genetically from cutaneous and uveal melanoma. As they respond poorly to available treatment regimens, novel effective therapeutic approaches for affected patients are urgently needed. PMID: 32064597 [PubMed - as supplied by publisher]
Source: The British Journal of Dermatology - Category: Dermatology Authors: Tags: Br J Dermatol Source Type: research
In melanoma, the lymphocytic infiltrate is a prognostic parameter classified morphologically into 'brisk', 'non-brisk' and 'absent' entailing a functional association that has never been proved. Recently, it has been shown that lymphocytic populations can be very heterogeneous, and that anti-PD-1 immunotherapy supports activated T cells. Here, we characterize the immune landscape in primary melanoma by high-dimensional single cell multiplex analysis in tissue sections (MILAN technique) followed by image analysis, RT-PCR and shotgun proteomics. We observed that the brisk and non-brisk patterns are heterogeneous functional c...
Source: eLife - Category: Biomedical Science Tags: Cancer Biology Source Type: research
T cell cancer neoantigens are created from peptides derived from cancer-specific aberrant proteins, such as mutated and fusion proteins, presented in complex with human leukocyte antigens on the cancer cell surface. Because expression of the aberrant target protein is exclusive to malignant cells, immunotherapy directed against neoantigens should avoid “on-target, off-tumor” toxicity. The efficacy of neoantigen vaccines in melanoma and glioblastoma and of adoptive transfer of neoantigen-specific T cells in epithelial tumors indicates that neoantigens are valid therapeutic targets. Improvements in sequencing tec...
Source: Frontiers in Immunology - Category: Allergy & Immunology Source Type: research
Contributor : Peng ShenSeries Type : Expression profiling by RT-PCROrganism : Homo sapiensRecent development of integrative therapy against melanoma combines surgery, radiotherapy, targeted therapy, and immunotherapy; however, the clinical outcomes of advanced stage and recurrent melanoma are poor. As a skin cancer, melanoma is generally resistant to radiotherapy. Hence, there is an urgent need for evaluation of the mechanisms of radioresistance. The present study identified miR-335 as one of the differential expression of miRNAs in recurrent melanoma biopsies post-radiotherapy. The expression of miR-335 declined in melano...
Source: GEO: Gene Expression Omnibus - Category: Genetics & Stem Cells Tags: Expression profiling by RT-PCR Homo sapiens Source Type: research
Abstract CDK9 is an important cell-cycle control enzyme essential in transcription, elongation, and mRNA maturation. Overexpression of CDK9 has been reported in several diseases, including acute lymphoblastic leukemia, chronic lymphocytic leukemia, and malignant melanoma. Recent research revealed that CDK9-inhibitors have a major impact on the induction of apoptosis in hepatocellular carcinoma (HCC) cell lines. Despite surprisingly promising results in in vitro and in vivo research, no CDK9 related therapy is currently allowed in cases of HCC. Furthermore, due to their high specificity, the inhibitors had no effec...
Source: Current Cancer Drug Targets - Category: Cancer & Oncology Authors: Tags: Curr Cancer Drug Targets Source Type: research
ConclusionT-VEC represents an effective and tolerable treatment option. This is true not only for loco-regionally advanced melanoma patients, but also for patients with stable or regressive systemic metastases who develop loco-regionally acquired resistance upon treatment with immune checkpoint blockade or targeted therapy. A sensible selection of suitable patients seems to be crucial.
Source: Cancer Immunology, Immunotherapy - Category: Cancer & Oncology Source Type: research
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