Combining onartuzumab with erlotinib inhibits growth of non-small cell lung cancer with activating EGFR mutations and HGF overexpression.

Erlotinib, a tyrosine kinase inhibitor of the epidermal growth factor receptor (EGFR-TKI), benefits survival of patients with non-small cell lung cancer (NSCLC) who harbor activating EGFR mutations. However, elevated expression of hepatocyte growth factor (HGF), a ligand of the MET receptor tyrosine kinase, causes erlotinib resistance. Because onartuzumab, a monovalent antibody to MET, blocks HGF-induced MET activation, the addition of onartuzumab to erlotinib may improve therapeutic efficacy. We engineered the human NSCLC cell line PC-9 (MET-positive cells harboring an exon 19 deletion of EGFR) to overexpress hHGF and evaluated the effects of an onartuzumab and erlotinib combination in vitro and in vivo in xenograft models. A stable clone of PC-9/hHGF was less sensitive to erlotinib than the parental PC-9, and the addition of onartuzumab to erlotinib suppressed the proliferation of these cells in vitro. In PC-9/hHGF xenograft tumors, onartuzumab or erlotinib alone minimally inhibited tumor growth; however, combining onartuzumab and erlotinib markedly suppressed tumor growth. The total MET protein level was decreased in PC-9/hHGF cells, because MET is constitutively phosphorylated by autocrine HGF, leading to its ubiquitination and degradation. Onartuzumab reduced phospho-MET levels, inhibited MET ubiquitination, and consequently restored MET protein levels. Moreover, in NSCLC clinical specimens harboring activating EGFR mutations, more than 30% of patients expressed high levels of HGF. Our findings raised the possibility that patients with NSCLC with EGFR mutations who express high levels of HGF may benefit from onartuzumab and erlotinib combination therapy, and that HGF can be a novel biomarker for selecting such patients.

Altered RNA editing of serotonin 2C receptor in a rat model of depression.

Altered RNA editing of serotonin 2C receptor (HTR2C) has been suggested to be involved in the pathophysiology of major depression. Here we examined RNA editing status of HTR2C in the learned helplessness (LH) rats, one of well-established animal models of depression. LH rats showed the significantly increased RNA editing of site E, and tendency for increased RNA editing of other editing sites. Treatment with fluoxetine, a selective serotonin reuptake inhibitor, or imipramine, a tricyclic antidepressant, affected the RNA editing status of the LH rats. Although, these antidepressants differentially altered RNA editing status, they commonly reduced RNA editing efficiency of site E. We further revealed that altered RNA editing in the LH rats and by antidepressants was not explained by altered expression of RNA editing enzymes or their substrates (adenosine deaminases that act on RNA, HTR2C, and spliced form of HTR2C). These results suggest that alteration of RNA editing of HTR2C may play a role in the pathophysiology of depression and action of antidepressants.