Dual Inhibition of MEK and PI3K/Akt Rescues Cancer Cachexia through both Tumor-Extrinsic and -Intrinsic Activities.
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.
Arthur G. James Comprehensive Cancer Center Cancer Cachexia Program, The Ohio State University Medical Center, Columbus, Ohio 43210, USA.|Department of Molecular Virology, Immunology, and Medical Genetics, The Ohio State University Medical Center, Columbus, Ohio 43210, USA.
Erin E
EE
Talbert
Arthur G. James Comprehensive Cancer Center Cancer Cachexia Program, The Ohio State University Medical Center, Columbus, Ohio 43210, USA.|Molecular, Cellular, and Developmental Biology Program, The Ohio State University Medical Center, Columbus, Ohio 43210, USA.
Jennifer
J
Yang
Arthur G. James Comprehensive Cancer Center Cancer Cachexia Program, The Ohio State University Medical Center, Columbus, Ohio 43210, USA.|Department of Internal Medicine, Division of Medical Oncology, The Ohio State University Medical Center, Columbus, Ohio 43210, USA.
Thomas A
TA
Mace
Arthur G. James Comprehensive Cancer Center Cancer Cachexia Program, The Ohio State University Medical Center, Columbus, Ohio 43210, USA.|Department of Internal Medicine, Division of Medical Oncology, The Ohio State University Medical Center, Columbus, Ohio 43210, USA.
Matthew R
MR
Farren
Pathology & Laboratory Medicine, Emory University School of Medicine, Atlanta, Georgia 30307, USA.
Alton B
AB
Farris
Center for Biostatistics, The Ohio State University Medical Center, Columbus, Ohio 43210, USA.
Gregory S
GS
Young
Department of Internal Medicine, Division of Medical Oncology, The Ohio State University Medical Center, Columbus, Ohio 43210, USA.
Omar
O
Elnaggar
Department of Internal Medicine, Division of Medical Oncology, The Ohio State University Medical Center, Columbus, Ohio 43210, USA.
Zheng
Z
Che
Arthur G. James Comprehensive Cancer Center Cancer Cachexia Program, The Ohio State University Medical Center, Columbus, Ohio 43210, USA.
Cynthia D
CD
Timmers
Arthur G. James Comprehensive Cancer Center Cancer Cachexia Program, The Ohio State University Medical Center, Columbus, Ohio 43210, USA.
Priyani
P
Rajasekera
Biomedical Science Program, The Ohio State University Medical Center, Columbus, Ohio 43210, USA.
Jennifer M
JM
Maskarinec
Arthur G. James Comprehensive Cancer Center Cancer Cachexia Program, The Ohio State University Medical Center, Columbus, Ohio 43210, USA.|Division of Surgical Oncology, The Ohio State University Medical Center, Columbus, Ohio 43210, USA.
Mark
M
Bloomston
Arthur G. James Comprehensive Cancer Center Cancer Cachexia Program, The Ohio State University Medical Center, Columbus, Ohio 43210, USA.
Tanios
T
Bekaii-Saab
Arthur G. James Comprehensive Cancer Center Cancer Cachexia Program, The Ohio State University Medical Center, Columbus, Ohio 43210, USA.|Department of Molecular Virology, Immunology, and Medical Genetics, The Ohio State University Medical Center, Columbus, Ohio 43210, USA.|Molecular, Cellular, and Developmental Biology Program, The Ohio State University Medical Center, Columbus, Ohio 43210, USA.
Denis C
DC
Guttridge
Arthur G. James Comprehensive Cancer Center Cancer Cachexia Program, The Ohio State University Medical Center, Columbus, Ohio 43210, USA.|Department of Internal Medicine, Division of Medical Oncology, The Ohio State University Medical Center, Columbus, Ohio 43210, USA.
Gregory B
GB
Lesinski
D000631:Aminopyridines / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001562:Benzimidazoles / Q000494:pharmacology; D015415:Biomarkers; D001835:Body Weight / Q000187:drug effects; D002100:Cachexia / Q000188:drug therapy / Q000209:etiology* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D006801:Humans; D051379:Mice; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009025:Morpholines / Q000494:pharmacology; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D023041:Xenograft Model Antitumor Assays
D000631:Aminopyridines; D000970:Antineoplastic Agents; D001562:Benzimidazoles; D015415:Biomarkers; D020929:Mitogen-Activated Protein Kinase Kinases; D009025:Morpholines; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; C571178:NVP-BKM120; C581313:binimetinib