Phospho-ERK is a biomarker of response to a synthetic lethal drug combination of sorafenib and MEK inhibition in liver cancer

Abstract

Sorafenib is approved as the standard therapy for patients with advanced hepatocellular carcinoma, but only provides limited survival benefit. Herein, we found that inhibition of the kinase ERK2 increases the response to sorafenib in liver cancer. Our data indicate that a combination of sorafenib and a MEK inhibitor is most likely to be effective in tumors with high basal phospho-ERK levels.

Vessels That Encapsulate Tumor Clusters (VETC) Pattern Is a Predictor of Sorafenib Benefit in Patients with Hepatocellular Carcinoma

“…Whether they were associated with the different survival benefit of sorafenib therapy was then analyzed. Phosphorylation of ERK, a key downstream event in both Raf‐MEK‐ERK and VEGFA‐VEGFR2‐ERK signaling pathways, was detected in VETC + and VETC – HCC tissues (Fig. A).…”

“…We next explored the mechanism underlying the different survival benefit of sorafenib treatment for VETC + and VETC – HCC. Activation of Raf/mitogen‐activated protein kinase kinase (MEK)/ERK and vascular endothelial growth factor (VEGF) A/VEGF receptor 2 (VEGFR2)/ERK signaling pathways or induction of autophagy has been shown to affect the therapeutic effect of sorafenib . Whether they were associated with the different survival benefit of sorafenib therapy was then analyzed.…”

Analysis of Liver Cancer Cell Lines Identifies Agents With Likely Efficacy Against Hepatocellular Carcinoma and Markers of Response

“…36 Our study has also highlighted a synergistic effect of sorafenib in combination with MEK1/2 inhibitors with higher sensitivity in the CL1 and CL2 subgroups of LCCL, in lines with recent studies in HCC preclinical models and in HCC patients. 37,38 Our screening also identified potential new attractive drugs already approved in the clinics in specific molecular contexts. Our results showed responses in LCCL harboring inactivating mutations in TSC1 or TSC2 treated by an mTOR inhibitor, suggesting that the 7% of HCC demonstrating the same alterations could benefit from rapamycin or alternative inhibitors, in line with previous reports (Figure 7).…”

Are we ready for targeted therapy combinations in HCC?

“…This is one of a series of papers in which Rene Bernards and colleagues reveal the potential of CRISPR screens for discovering therapeutic targets in HCC 5 8–11. In line with Zender’s shRNA screen, one of these papers confirmed that combining sorafenib with MEK inhibition could be beneficial in some HCCs 10. In a very recent study,9 they used a sequential screen strategy: they first performed a CRISPR screen to identify agents that induce senescence in HCC cells, and then used a drug screen to look for agents that selectively kill senescent HCC cells.…”

“…This is one of a series of papers in which Rene Bernards and colleagues reveal the potential of CRISPR screens for discovering therapeutic targets in HCC 5 8–11. In line with Zender’s shRNA screen, one of these papers confirmed that combining sorafenib with MEK inhibition could be beneficial in some HCCs 10.…”