Abstract
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) can induce apoptosis in many cancer cells without causing toxicity in vivo. However, to date, TRAIL-receptor agonists have only shown limited therapeutic benefit in clinical trials. This can, most likely, be attributed to the fact that 50% of all cancer cell lines and most primary human cancers are TRAIL resistant. Consequently, future TRAIL-based therapies will require the addition of sensitizing agents that remove crucial blocks in the TRAIL apoptosis pathway. Here, we identify PIK-75, a small molecule inhibitor of the p110α isoform of phosphoinositide-3 kinase (PI3K), as an exceptionally potent TRAIL apoptosis sensitizer. Surprisingly, PI3K inhibition was not responsible for this activity. A kinome-wide in vitro screen revealed that PIK-75 strongly inhibits a panel of 27 kinases in addition to p110α. Within this panel, we identified cyclin-dependent kinase 9 (CDK9) as responsible for TRAIL resistance of cancer cells. Combination of CDK9 inhibition with TRAIL effectively induced apoptosis even in highly TRAIL-resistant cancer cells. Mechanistically, CDK9 inhibition resulted in downregulation of cellular FLICE-like inhibitory protein (cFlip) and Mcl-1 at both the mRNA and protein levels. Concomitant cFlip and Mcl-1 downregulation was required and sufficient for TRAIL sensitization by CDK9 inhibition. When evaluating cancer selectivity of TRAIL combined with SNS-032, the most selective and clinically used inhibitor of CDK9, we found that a panel of mostly TRAIL-resistant non-small cell lung cancer cell lines was readily killed, even at low concentrations of TRAIL. Primary human hepatocytes did not succumb to the same treatment regime, defining a therapeutic window. Importantly, TRAIL in combination with SNS-032 eradicated established, orthotopic lung cancer xenografts in vivo. Based on the high potency of CDK9 inhibition as a cancer cell-selective TRAIL-sensitizing strategy, we envisage the development of new, highly effective cancer therapies.
Highlights
De novo and acquired resistance to conventional chemotherapy remains the major obstacle in treating many cancers today
When evaluating cancer selectivity of TNF-related apoptosisinducing ligand (TRAIL) combined with SNS-032, the most selective and clinically used inhibitor of cyclin-dependent kinase 9 (CDK9), we found that a panel of mostly TRAIL-resistant non-small cell lung cancer cell lines was readily killed, even at low concentrations of TRAIL
Whereas co-treatment with inhibitors of the b, g- and d-isoforms of phosphoinositide-3 kinase (PI3K) showed only marginal effects, co-treatment with PIK-75 profoundly increased TRAIL sensitivity of HeLa cells shifting the sensitivity of these cells by 3–4 orders of magnitude (Figure 1a and Supplementary Figure S1b)
Summary
De novo and acquired resistance to conventional chemotherapy remains the major obstacle in treating many cancers today. Attempts to use cell deathinducing CD95L or TNF for systemic therapy were hampered by severe toxicity.[2,3] In contrast, TNF-related apoptosisinducing ligand (TRAIL) can induce apoptosis selectively in tumor cells in vitro and in vivo.[4,5]. Based on these findings, TRAIL-receptor (TRAIL-R) agonists, comprising recombinant soluble TRAIL and agonistic TRAIL-R antibodies, are currently evaluated in clinical trials. These findings have encouraged extensive research into identifying potent TRAIL-sensitizing agents that do not sensitize nontransformed cells
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