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

Abstract

Involuntary weight loss, a part of the cachexia syndrome, is a debilitating co-morbidity 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 anti-cachectic. 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 is at least in part independent of the tumor. Because single agent MEK inhibitors have been limited as a front-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 anti-tumor activity. Thus, combinatorial therapy might serve as a new approach for the treatment of cancer cachexia.

Recent developments in the field of cachexia, sarcopenia, and muscle wasting: highlights from the 12th Cachexia Conference

“…Additionally, he showed that growth differentiation factor 15 (GDF‐15) is required for development of pancreatic cancer KPP and GDF‐15fl/fl mice exhibit a reduction in pancreatic cancer. Moreover, KPP mice at their endpoint exhibited decreased body weight compared with their littermate controls but, importantly, had similar tibia lengths, suggesting that the lower body weights of KPP mice were not due to a failure to grow . The KPP mouse as an improvement over existing animal models of cachexia and anticipate that KPP mice will prove to be a useful tool in improving our understanding of the mechanisms driving tissue wasting and in translating that understanding into new anti‐cachexia therapies …”

Recent developments in the field of cachexia, sarcopenia, and muscle wasting: highlights from the 11th Cachexia Conference

“…(Department of Cancer Biology and Genetics, The Ohio State University Wexner Medical Center, Columbus, OH, USA) gave an overview to the important functions of NF‐κB in myoblast to stimulate activin and inhibit muscle differentiation. They impressively showed that NF‐κB is activated in cachectic muscle in both paired box 7 progenitor cells and myofibers . Other studies buttress the view that increased forkhead box protein O (FoxO) signalling and the activation of the transcription factors NF‐κB, muscle RING finger 1 (MuRF1), and muscle atrophy F‐box (MAFbx) in skeletal muscle play major roles during cachexia onset and progression .…”

Silver linings on the horizon: highlights from the 10th Cachexia Conference

“…(Department of Cancer Biology and Genetics, The Ohio State University Wexner Medical Center, Columbus, OH, USA) gave an overview to the important functions of transcription factors nuclear factor κB (NF‐κB) in myoblast to stimulate activin and inhibit muscle differentiation. He impressively showed that NF‐κB is activated in cachectic muscle in both PAX 7 progenitor cells and myofibers . Other studies buttress the view that increased forkhead box protein O (FoxO) signalling and the activation of the transcription factors NF‐κB, MuRF1 and muscle atrophy F‐box (MAFbx) in skeletal muscle play major roles during cachexia onset and progression .…”