TY - JOUR
T1 - Dual inhibition of MEK and PI3K/Akt rescues cancer cachexia through both tumor-extrinsic and -intrinsic activities
AU - Talbert, Erin E.
AU - Yang, Jennifer
AU - Mace, Thomas A.
AU - Farren, Matthew R.
AU - Farris, Alton B.
AU - Young, Gregory S.
AU - Elnaggar, Omar
AU - Che, Zheng
AU - Timmers, Cynthia D.
AU - Rajasekera, Priyani
AU - Maskarinec, Jennifer M.
AU - Bloomston, Mark
AU - Bekaii-Saab, Tanios
AU - Guttridge, Denis C.
AU - Lesinski, Gregory B.
N1 - Publisher Copyright:
© 2016 American Association for Cancer Research.
PY - 2017/2
Y1 - 2017/2
N2 - 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.
AB - 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.
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U2 - 10.1158/1535-7163.MCT-16-0337
DO - 10.1158/1535-7163.MCT-16-0337
M3 - Article
C2 - 27811010
AN - SCOPUS:85011649886
SN - 1535-7163
VL - 16
SP - 344
EP - 356
JO - Molecular cancer therapeutics
JF - Molecular cancer therapeutics
IS - 2
ER -