B-Raf and MEK inhibitors differentially regulate cell fate and microenvironment in human hepatocellular carcinoma
Menée sur des lignées cellulaires et des échantillons de tissu tumoral et de tissu sain prélevés sur des patients atteints d'un carcinome hépatocellulaire, cette étude identifie des biomarqueurs du micro-environnement tumoral associés à la réponse à divers inhibiteurs de Braf ou MEK
Purpose: Small molecule inhibitors of the mitogen activated protein kinase (MAPK) pathway like sorafenib represent novel treatment options for advanced hepatocellular carcinoma (HCC). The aim of our study was to identify downstream targets as biomarker candidates that are directly linked to the oncogenic MAPK pathway in HCC and correlate with inhibition of this pathway by multi-kinase inhibitors.
Experimental Design: HCC cell lines and fresh tumor and tumor-free liver tissues from HCC patients were incubated with different BRaf or MEK inhibitors and analyzed for kinase phosphorylation, proliferation, induction of apoptosis and chemokine secretion.
Results: HCC cell lines responded differentially to these inhibitors in a dose-dependent manner even those targeting the same kinase. Sorafenib inhibited both MEK1 and ERK1/2 phosphorylation at high but increased signaling at low concentrations. Similarly, PLX4720 increased MEK/ERK signaling independently from mutations in BRaf or NRas. MEK inhibitors decreased ERK1/2 phosphorylation in a dose-dependent manner. These signaling characteristics correlated with inhibition of proliferation, induction of apoptosis and chemokine secretion. Fresh tissues derived from patients diagnosed with primary HCC responded to these inhibitors with changes in their microenvironment following the patterns observed in HCC cells.
Conclusions: Oncogenic signaling of the MAPK pathway influences HCC sensitivity to treatment with BRaf and MEK inhibitors regarding cell fate independently from mutations in BRaf and NRas. MAPK inhibitors have strong impact on chemokine secretion as consequence of interference with oncogenic signaling. Therefore, novel biomarker candidates associated with HCC microenvironment may be developed for prediction and monitoring of treatment response to small molecule inhibitors.
Clinical Cancer Research , résumé, 2014