Journal article
Dual Inhibition of MEK and PI3K/Akt Rescues Cancer Cachexia through both Tumor-Extrinsic and - Intrinsic Activities
Molecular cancer therapeutics, Vol.16(2), pp.344-356
02/01/2017
DOI: 10.1158/1535-7163.MCT-16-0337
PMCID: PMC5292063
PMID: 27811010
Abstract
Involuntary weight loss, a part of the cachexia syndrome, is a debilitating comorbidity of cancer and currently has no treatment options. Results from a recent clinical trial at our institution showed that biliary tract cancer patients treated with a MEK inhibitor exhibited poor tumor responses but surprisingly gained weight and increased their skeletal muscle mass. This implied that MEKinhibition might be anticachectic. To test this potential effect of MEK inhibition, we utilized the established Colon-26 model of cancer cachexia and the MEK1/2 inhibitor MEK162. Results showed that MEK inhibition effectively prevented muscle wasting. Importantly, MEK162 retained its ability to spare muscle loss even in mice bearing a Colon-26 clone resistant to the MEK inhibitor, demonstrating that the effects of blocking MEK are at least in part independent of the tumor. Because single-agent MEK inhibitors have been limited as a first-line targeted therapy due to compensatory activation of other oncogenic signaling pathways, we combined MEK162 with the PI3K/Akt inhibitor buparlisib. Results showed that this combinatorial treatment significantly reduced tumor growth due to a direct activity on Colon-26 tumor cells in vitro and in vivo, while also preserving skeletal muscle mass. Together, our results suggest that as a monotherapy, MEK inhibition preserves muscle mass, but when combined with a PI3K/Akt inhibitor exhibits potent antitumor activity. Thus, combinatorial therapy might serve as a new approach for the treatment of cancer cachexia.
Details
- Title: Subtitle
- Dual Inhibition of MEK and PI3K/Akt Rescues Cancer Cachexia through both Tumor-Extrinsic and - Intrinsic Activities
- Creators
- Erin E. Talbert - The Ohio State UniversityJennifer Yang - The Ohio State UniversityThomas A. Mace - The Ohio State UniversityMatthew R. Farren - The Ohio State UniversityAlton B. Farris - Emory UniversityGregory S. Young - The Ohio State UniversityOmar Elnaggar - The Ohio State UniversityZheng Che - The Ohio State UniversityCynthia D. Timmers - The Ohio State UniversityPriyani Rajasekera - The Ohio State UniversityJennifer M. Maskarinec - The Ohio State UniversityMark Bloomston - The Ohio State UniversityTanios Bekaii-Saab - The Ohio State UniversityDenis C. Guttridge - The Ohio State UniversityGregory B. Lesinski - The Ohio State University
- Resource Type
- Journal article
- Publication Details
- Molecular cancer therapeutics, Vol.16(2), pp.344-356
- Publisher
- Amer Assoc Cancer Research
- DOI
- 10.1158/1535-7163.MCT-16-0337
- PMID
- 27811010
- PMCID
- PMC5292063
- ISSN
- 1535-7163
- eISSN
- 1538-8514
- Number of pages
- 13
- Grant note
- Weiss Postdoctoral Fellowship PF-15-156-01-CSM; NIHT32CA106196; T32CA090223; R01 CA180057 / American Cancer Society R01CA180057 / NATIONAL CANCER INSTITUTE; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI) U24DK100469 / NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Diabetes & Digestive & Kidney Diseases (NIDDK) Ohio State University Comprehensive Cancer Center Pelotonia Fellowship Program William Hall Fund for Liver and Pancreatic Cancer Research Division of Medical Oncology Array Biopharma, Inc.
- Language
- English
- Date published
- 02/01/2017
- Academic Unit
- Fraternal Order of Eagles Diabetes Research Center; Health and Human Physiology; Internal Medicine
- Record Identifier
- 9984259399402771
Metrics
14 Record Views