Dataset Information

MCL1 inhibitors S63845/MIK665 plus Navitoclax synergistically kill difficult-to-treat melanoma cells.

ABSTRACT: Current treatment for patients with metastatic melanoma include molecular-targeted therapies and immune checkpoint inhibitors. However, a subset of melanomas are difficult-to-treat. These melanomas include those without the genetic markers for targeted therapy, non-responsive to immunotherapy, and those who have relapsed or exhausted their therapeutic options. Therefore, it is necessary to understand and explore other biological processes that may provide new therapeutic approaches. One of most appealing is targeting the apoptotic/anti-apoptotic system that is effective against leukemia. We used genetic knockdown and pharmacologic approaches of BH3 mimetics to target anti-apoptotic BCL2 family members and identified MCL1 and BCLXL as crucial pro-survival members in melanoma. We then examined the effects of combining BH3 mimetics to target MCL1 and BCLXL in vitro and in vivo. These include clinical-trial-ready compounds such as ABT-263 (Navitoclax) and S63845/S64315 (MIK655). We used cell lines derived from patients with difficult-to-treat melanomas. In vitro, the combined inhibition of MCL1 and BCLXL resulted in significantly effective cell killing compared to single-agent treatment (p??0.40). Taken together, this study suggests that dual targeting of MCL1 and BCLXL should be considered as a treatment option for difficult-to-treat melanoma patients.

SUBMITTER: Mukherjee N

PROVIDER: S-EPMC7280535 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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MCL1 inhibitors S63845/MIK665 plus Navitoclax synergistically kill difficult-to-treat melanoma cells.

Mukherjee Nabanita N Skees Jenette J Todd Kaleb J KJ West Drake A DA Lambert Karoline A KA Robinson William A WA Amato Carol M CM Couts Kasey L KL Van Gulick Robert R MacBeth Morgan M Nassar Kelsey K Tan Aik-Choon AC Zhai Zili Z Fujita Mayumi M Bagby Stacey M SM Dart Chiara R CR Lambert James R JR Norris David A DA Shellman Yiqun G YG

Cell death & disease 20200608 6

Current treatment for patients with metastatic melanoma include molecular-targeted therapies and immune checkpoint inhibitors. However, a subset of melanomas are difficult-to-treat. These melanomas include those without the genetic markers for targeted therapy, non-responsive to immunotherapy, and those who have relapsed or exhausted their therapeutic options. Therefore, it is necessary to understand and explore other biological processes that may provide new therapeutic approaches. One of most ...[more]

PMID: 32513939

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Project description:ObjectiveRecently, several academics have recommended that the concept of difficult-to-treat depression (DTD) should be considered in some of the cases where achieving or maintaining remission of depressive symptoms is not possible. In 2020, a consensus statement, not based on a formal process and systematic review defined difficult-to-treat depression as "depression that continues to cause significant burden despite normal treatment efforts". In addition to addressing symptom control, interventions for DTD should also target other factors, including the management of psychiatric and medical comorbidities, psychosocial functioning, self-esteem, and self-management strategies. The purpose of this scoping review is to explore the scientific literature, which is still unclear and vague, regarding the pathophysiology and treatment of difficult-to-treat depression, providing a summary of its current conceptualization. This represents a cultural and scientific shift that offers clinicians and researchers valid and up-to-date study criteria, thus expanding upon the model of treatment-resistant depression (TRD). Consequently contributions, concepts, theories and gaps of the state of the art in the description of difficult-to-treat depression have been summarized here.MethodA research study was conducted using PubMed, Scopus, PsycINFO, Cochrane Library, and Open Grey databases to identify and examine articles reporting key features related to the recent concept of difficult-to-treat depression. The research covered a period of time between January 1, 2013, and March 1, 2023. Based on a formal checklist, two researchers independently assessed the eligibility criteria to determine which studies to include or exclude in this search. Further data evaluations were conducted for the articles that were deemed to have the most comprehensive descriptions.ResultsThe results of the research yielded a body of literature that provides a clear definition of difficult-to-treat depression and insights into its clinical application and research perspective.ConclusionsDTD represents a cultural and scientific shift that provides clinicians and researchers with valid and up-to-date study criteria that allow the extension of the treatment-resistant depression (TRD) model. The main difference lies in the operational process of assessment and intervention in the depressive syndrome in relation to the search for a therapeutic response. The results of this review show that DTD is a theoretically and clinically useful conceptualization for depressive syndromes that are not just simply resistant to treatment. This clinical condition entails a novel clinical therapeutic approach for specific patients and may be used throughout the world to help recognize this clinical condition while optimizing overall care for these patients. However, as we have highlighted, in the absence of RCTs and further observational studies, it is desirable that DTD be further investigated and defined..

Dataset Information

MCL1 inhibitors S63845/MIK665 plus Navitoclax synergistically kill difficult-to-treat melanoma cells.

Publications

MCL1 inhibitors S63845/MIK665 plus Navitoclax synergistically kill difficult-to-treat melanoma cells.

Similar Datasets

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