Sorafenib synergizes with metformin in NSCLC through AMPK pathway activation

Abstract

The multikinase inhibitor sorafenib is under clinical investigation for the treatment of many solid tumors, but in most cases, the molecular target responsible for the clinical effect is unknown. Furthermore, enhancing the effectiveness of sorafenib using combination strategies is a major clinical challenge. Here, we identify sorafenib as an activator of AMP-activated protein kinase (AMPK), in a manner that involves either upstream LKB1 or CAMKK2. We further show in a phase II clinical trial in KRAS mutant advanced non-small cell lung cancer (NSCLC) with single agent sorafenib an improved disease control rate in patients using the antidiabetic drug metformin. Consistent with this, sorafenib and metformin act synergistically in inhibiting cellular proliferation in NSCLC in vitro and in vivo. A synergistic effect of both drugs is also seen on phosphorylation of the AMPKα activation site. Our results provide a rationale for the synergistic antiproliferative effects, given that AMPK inhibits downstream mTOR signaling. These data suggest that the combination of sorafenib with AMPK activators could have beneficial effects on tumor regression by AMPK pathway activation. The combination of metformin or other AMPK activators and sorafenib could be tested in prospective clinical trials.

Induction of apoptosis by ethanol extract of <i>Evodia rutaecarpa</i> in HeLa human cervical cancer cells <i>via</i> activation of AMP-activated protein kinase

“…We suggest that AMPK plays a pivotal role in mitochondria-mediated apoptosis in response to EEER treatment. In support of our suggestion, recent clinical trials have demonstrated that metformin, an AMPK activator, decreased the incidence of cancer and cancer-related mortality and improved the disease control rate by itself or in combination with another drug (49). Although the active compound of EEER and the exact mechanism through which AMPK is activated should be further elucidated, our results suggest E. rutaecarpa is a prospective clinical option to treat human cervical cancer.…”

Synergistic effect of metformin on sorafenib in in vitro study using hepatocellular carcinoma cell lines

“…A clinical study showed that patients with KRAS -mutant advanced non-small cell lung cancer receiving a combination of sorafenib and metformin had better outcomes than those receiving sorafenib alone. The study also showed that sorafenib and metformin act synergistically through inhibiting cellular proliferation in non-small cell lung cancer in vitro and in vivo and by phosphorylating the AMPK α activation site 19. Our in vitro study also demonstrated synergistic antitumor effects of both drugs.…”

Heterogeneity of epidermal growth factor receptor signalling networks in glioblastoma

“…A number of mechanisms seem to have an important role in the development of resistance to RTK-targeted therapies, including insufficient drug exposure; second-site resistance-promoting mutations in the targeted RTK; mutations in downstream signalling effectors that keep the pathway activated; and bypass mechanisms through the amplification, mutation or upregulation of another RTK or its downstream effectors 72 .…”