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      Skeletal muscle anabolism is a side effect of therapy with the MEK inhibitor: selumetinib in patients with cholangiocarcinoma

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          Abstract

          Background:

          Cancer cachexia is characterised by skeletal muscle wasting; however, potential for muscle anabolism in patients with advanced cancer is unproven.

          Methods:

          Quantitative analysis of computed tomography images for loss/gain of muscle in cholangiocarcinoma patients receiving selumetinib (AZD6244; ARRY-142886) in a Phase II study, compared with a separate standard therapy group. Selumetinib is an inhibitor of mitogen-activated protein/extracellular signal–regulated kinase and of interleukin-6 secretion, a putative mediator of muscle wasting.

          Results:

          Overall, 84.2% of patients gained muscle after initiating selumetinib; mean overall gain of total lumbar muscle cross-sectional area was 13.6 cm 2/100 days (∼2.3 kg on a whole-body basis). Cholangiocarcinoma patients who began standard treatment were markedly catabolic, with overall muscle loss of −7.3 cm 2/100 days (∼1.2 kg) and by contrast only 16.7% of these patients gained muscle.

          Conclusion:

          Our findings suggest that selumetinib promotes muscle gain in patients with cholangiocarcinoma. Specific mechanisms and relevance for cachexia therapy remain to be investigated.

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          Most cited references18

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          Reversal of cancer cachexia and muscle wasting by ActRIIB antagonism leads to prolonged survival.

          Xiaolan Zhou, Jin Wang, John Lu … (2010)
          Muscle wasting and cachexia have long been postulated to be key determinants of cancer-related death, but there has been no direct experimental evidence to substantiate this hypothesis. Here, we show that in several cancer cachexia models, pharmacological blockade of ActRIIB pathway not only prevents further muscle wasting but also completely reverses prior loss of skeletal muscle and cancer-induced cardiac atrophy. This treatment dramatically prolongs survival, even of animals in which tumor growth is not inhibited and fat loss and production of proinflammatory cytokines are not reduced. ActRIIB pathway blockade abolished the activation of the ubiquitin-proteasome system and the induction of atrophy-specific ubiquitin ligases in muscles and also markedly stimulated muscle stem cell growth. These findings establish a crucial link between activation of the ActRIIB pathway and the development of cancer cachexia. Thus ActRIIB antagonism is a promising new approach for treating cancer cachexia, whose inhibition per se prolongs survival. Copyright 2010 Elsevier Inc. All rights reserved.
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            Akt maintains cell size and survival by increasing mTOR-dependent nutrient uptake.

            B Taylor Thompson, Kassandra Edinger (2002)
            In multicellular organisms, constituent cells depend on extracellular signals for growth, proliferation, and survival. When cells are withdrawn from growth factors, they undergo apoptosis. Expression of constitutively active forms of the serine/threonine kinase Akt/PKB can prevent apoptosis upon growth factor withdrawal. Akt-mediated survival depends in part on the maintenance of glucose metabolism, suggesting that reduced glucose utilization contributes to growth factor withdrawal-induced death. However, it is unclear how restricting access to extracellular glucose alone would lead to the metabolic collapse observed after growth factor withdrawal. We report herein that growth factor withdrawal results in the loss of surface transporters for not only glucose but also amino acids, low-density lipoprotein, and iron. This coordinated decline in transporters and receptors for extracellular molecules creates a catabolic state characterized by atrophy and a decline in the mitochondrial membrane potential. Activated forms of Akt maintained these transporters on the cell surface in the absence of growth factor through an mTOR-dependent mechanism. The mTOR inhibitor rapamycin diminished Akt-mediated increases in cell size, mitochondrial membrane potential, and cell survival. These results suggest that growth factors control cellular growth and survival by regulating cellular access to extracellular nutrients in part by modulating the activity of Akt and mTOR.
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              Body composition in patients with non-small cell lung cancer: a contemporary view of cancer cachexia with the use of computed tomography image analysis.

              Tony Reiman, S Antoun, Ioannis Gioulbasanis … (2010)
              The prominent clinical feature of cachexia has traditionally been understood to be weight loss; however, in recognition of the potential for divergent behavior of muscle and adipose tissue, cachexia was recently defined as loss of muscle with or without loss of fat mass. Detailed assessments are required to verify body composition in patients with cancer cachexia. We adopted a population-based approach to study body composition in patients with cancer, with the use of diagnostic computed tomography images acquired for cancer diagnosis and follow-up. A prospective cohort of 441 patients with non-small cell lung cancer, who were referred consecutively to a regional medical oncology service in Alberta, Canada, was evaluated. At referral (median time to death: 265 d), mean body mass index (BMI; in kg/m(2)) was 24.9, with 47.4% of patients being overweight or obese. Only 7.5% overall were underweight as conventionally understood (BMI < 18.5). Analysis of computed tomography images showed extremely high heterogeneity of muscle mass within all strata of BMI. The overall prevalence of severe muscle depletion (sarcopenia) was 46.8% and was present in patients in all BMI categories. A much higher proportion of men (61%) than women (31%) met the criteria for sarcopenia. Wasting of skeletal muscle is a prominent feature of patients with lung cancer, despite normal or heavy body weights. The significance of muscle wasting in normal-weight, overweight, and obese patients as a nutritional risk factor, as a prognostic factor, and as a predictor of cancer treatment toxicity is discussed in this article.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Br J Cancer
                Journal ID (iso-abbrev): Br. J. Cancer
                Title: British Journal of Cancer
                Publisher: Nature Publishing Group
                ISSN (Print): 0007-0920
                ISSN (Electronic): 1532-1827
                Publication date (Print): 08 May 2012
                Publication date (Electronic): 17 April 2012
                Volume: 106
                Issue: 10
                Pages: 1583-1586
                Affiliations
                [1 ]Department of Oncology, University of Alberta, Cross Cancer Institute , 11560 University Avenue, Edmonton, Alberta T6G 1Z2, Canada
                [2 ]Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center , A454 Starling Loving Hall, 320 West 10th Avenue, Columbus, OH 43210, USA
                [3 ]Department of Pharmacology, The Ohio State University Comprehensive Cancer Center , A454 Starling Loving Hall, 320 West 10th Avenue, Columbus, OH 43210, USA
                [4 ]Division of Cancer Treatment and Diagnosis , NCI, Executive Plaza North, Suite 7122 6130 Executive Blvd., Bethesda, MD 20892-7426, USA
                Author notes
                Article
                Publisher Item ID: bjc2012144
                DOI: 10.1038/bjc.2012.144
                PMC ID: 3349178
                PubMed ID: 22510747
                SO-VID: e6e9636c-daf9-47f5-af1d-94e5e7670bb5
                Copyright © Copyright © 2012 Cancer Research UK
                History
                Date revision received : 15 March 2012
                Date accepted : 21 March 2012
                Categories
                Subject: Short Communication

                ScienceOpen disciplines: Oncology & Radiotherapy
                Keywords: cholangiocarcinoma,skeletal muscle,cachexia,interleukin-6
                Data availability:
                ScienceOpen disciplines: Oncology & Radiotherapy
                Keywords: cholangiocarcinoma, skeletal muscle, cachexia, interleukin-6

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