Abstract
TNF-related apoptosis-inducing ligand (TRAIL) induces apoptosis through the death receptors (DRs) 4 and/or 5 expressed on the cell surface. Multiple clinical trials are underway to evaluate the antitumor activity of recombinant human TRAIL and agonistic antibodies to DR4 or DR5. However, their therapeutic potential is limited by the high frequency of cancer resistance. Here we provide evidence demonstrating the role of H-Ras in TRAIL receptor mediated apoptosis. By analyzing the genome wide mRNA expression data of the NCI60 cancer cell lines, we found that H-Ras expression was consistently upregulated in TRAIL-resistant cell lines. By contrast, no correlation was found between TRAIL sensitivity and K-Ras expression levels or their mutational profiles. Notably, H-Ras upregulation associated with a surface deficiency of TRAIL death receptors. Selective inhibition of H-Ras activity in TRAIL-resistant cells restored the surface expression of both DR4 and DR5 without changing their total protein levels. The resulting cells became highly susceptible to both TRAIL and agonistic DR5 antibody, whereas K-Ras inhibition had little or no effect on TRAIL-induced apoptosis, indicating H-Ras plays a distinct role in the regulation of TRAIL death receptors. Further studies are warranted to determine the therapeutic potential of H-Ras-specific inhibitors in combination with TRAIL receptor agonists.
Highlights
The outgrowth of cancer cells is a result of deregulated tissue homeostasis, which is tightly regulated through the delicate balance of cell growth and apoptosis [1]
We show that H-Ras is a key mediator of cancer resistance to TNF-related apoptosis inducing ligand (TRAIL) and anti-DR5 antibody
In the NCI60 panel, H-Ras mRNA levels inversely correlate with surface DR4/DR5 and cellular susceptibility to TRAIL-induced apoptosis
Summary
The outgrowth of cancer cells is a result of deregulated tissue homeostasis, which is tightly regulated through the delicate balance of cell growth and apoptosis [1]. A key strategy in the development of anticancer drugs has been to block the aberrant growth signaling components or to directly activate apoptosis machinery in cancer cells [2] This approach has resulted in several novel cancer therapies including humanized monoclonal antibodies directed against VEGF receptors [3, 4] or ErbB family of receptors [5]. The selectivity of TRAIL in killing cancer cells promoted multiple clinical trials to evaluate the potential antitumor activity of recombinant human TRAIL (e.g. dulanermin) and agonistic antibodies to DR4 (e.g. mapatumumab) or DR5 (e.g. lexatumumab, AMG 655, PRO95780, LBY135, and CS-1008) [2, 8, 9] These products have a well-tolerated safety profile in the completed Phase I studies [10,11,12,13]. An indepth analysis of resistance mechanisms could facilitate the identification of biomarkers for prediction of tumor response to the DR-targeted therapies and aid in the www.impactjournals.com/oncotarget
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