Dual Inhibition of MEK and PI3K/Akt Rescues Cancer Cachexia through both Tumor-Extrinsic and -Intrinsic Activities

• Published in: Molecular cancer therapeutics 2017-02, Vol.16 (2), p.344-356
• Main Authors: Talbert, Erin E, Yang, Jennifer, Mace, Thomas A, Farren, Matthew R, Farris, Alton B, Young, Gregory S, Elnaggar, Omar, Che, Zheng, Timmers, Cynthia D, Rajasekera, Priyani, Maskarinec, Jennifer M, Bloomston, Mark, Bekaii-Saab, Tanios, Guttridge, Denis C, Lesinski, Gregory B
• Format: Article
• Language: English
• Subjects: 1-Phosphatidylinositol 3-kinase; AKT protein; Aminopyridines - pharmacology; Animals; Anticancer properties; Antineoplastic Agents - pharmacology; Antitumor activity; Benzimidazoles - pharmacology; Biliary tract; Biomarkers; Body Weight - drug effects; Cachexia; Cachexia - drug therapy; Cachexia - etiology; Cachexia - pathology; Cancer; Cell Line, Tumor; Cell Proliferation - drug effects; Colon; Colon cancer; Combinatorial analysis; Disease Models, Animal; Humans; In vivo methods and tests; Inhibition; Inhibitors; MEK inhibitors; Mice; Mitogen-Activated Protein Kinase Kinases - antagonists & inhibitors; Mitogen-Activated Protein Kinase Kinases - metabolism; Morpholines - pharmacology; Muscle, Skeletal - drug effects; Muscle, Skeletal - metabolism; Muscle, Skeletal - pathology; Muscles; Musculoskeletal system; Neoplasms - drug therapy; Neoplasms - metabolism; Neoplasms - pathology; Phosphatidylinositol 3-Kinases - antagonists & inhibitors; Phosphatidylinositol 3-Kinases - metabolism; Protein Kinase Inhibitors - pharmacology; Proto-Oncogene Proteins c-akt - antagonists & inhibitors; Proto-Oncogene Proteins c-akt - metabolism; Signal Transduction - drug effects; Signaling; Skeletal muscle; Therapy; Tumor cells; Xenograft Model Antitumor Assays
• ISSN: 1535-7163; 1538-8514
• DOI: 10.1158/1535-7163.MCT-16-0337

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 MEK inhibition 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. Mol Cancer Ther; 16(2); 344-56. ©2016 AACRSee related article by Kobayashi et al., p. 357.