Pancreatic cancer remains one of the worst killers among human cancers, and new therapeutic options are urgently needed. In the current study we show that the novel multi-CDK inhibitor SCH727965 has considerable inhibitory effects on human pancreatic cancer cells in both in vitro and in vivo model systems. In vitro, SCH727965 inhibited growth, migration and colony formation of human pancreatic cancer cells through inhibition of cell cycle progression and decrease in Rb phosphorylation. These mechanisms were confirmed in vivo using immunohistochemistry on drug-treated low-passage subcutaneous pancreatic cancer xenograft tissue specimens. Important for pancreatic cancer, SCH727965 appears to significantly antagonize a critical effector pathway downstream of aberrant Ras signaling. Mutations within the KRAS2
gene are found in more than 90% of pancreatic cancers,21
and they are among the earliest genetic aberrations observed in low-grade PanIN lesions during the multistep progression model culminating in the development of a fully invasive pancreatic cancer phenotype.22
Taken together, these observations mark oncogenic Ras signaling as a prime therapeutic target in pancreatic cancer. In preclinical studies, disruption of KRAS2
function via RNA interference, antisense DNA or expression of dominant negative KRASN17
attenuates the tumorigenicity of pancreatic cancer cell lines.23–25
Unfortunately, strategies to inhibit the Ras pathway directly in patients have been largely unsuccessful, as exemplified by the lack of clinical activity of farnesyltransferase inhibitors (FTIs), which interfere with critical post-translational modification of RAS proteins.26
Ras signaling through the Ral pathway has emerged as a critical mediator of the malignant phenotype in pancreatic cancer cells,9,10
but there have been no effective strategies to inhibit Ral signaling. Our data presented here indicate that SCH727965 can block Ral activation in pancreatic cancer cells, potentially through inhibition of CDK5, which we have shown is an important determinant of Ras-mediated Ral activation in pancreatic cancer cells.11
In vivo, SCH727965 treatment dramatically reduced growth of a panel of 10 low-passage pancreatic cancer xenografts. There was a considerable amount of variation in the growth inhibitory effect of SCH727965 between the individual low-passage xenografts included in this study. It is tempting to speculate whether these differences in therapeutic response reflect variations in the underlying genetic alterations that might cause differences in the basal proliferation rates. Our own group and others have previously demonstrated that therapeutic response to drug treatment can be predicted by analysis of global gene expression patterns in many cases.16,27–30
Here, we found that the publicly available Gene Set Enrichment Analysis tool (www.broadinstitute.org/gsea/
) was able to readily identify control of cell cycle progression as one of the most highly enriched signaling pathways in SCH727965-sensitive vs. -resistant subcutaneous pancreatic cancer xenografts. In the xenografts showing the least sensitivity toward SCH727965 in terms of growth inhibition, the Notch- and TGFβ signaling pathways were among the top ten candidates thus identified. Both of these pathways are involved in pancreatic carcinogenesis and progression, and have long been suggested as promising therapeutic targets in pancreatic as well as in many other cancers.17,19,31–34
It is therefore tempting to speculate that concomitant pharmacological inhibition of either of these pathways, for which experim ental small molecule inhibitors are readily available to date, might prove to be a suitable strategy to overcome resistance to SCH727965 and enhance therapeutic potency in future studies.
In conclusion, these current data suggest that treatment with the novel, well-tolerated cyclin-dependent kinase inhibitor SCH727965 appears to be a promising new treatment option for pancreatic cancer with novel inhibitory effects on Ras-mediated Ral activation. Rapid evaluation of this strategy in a clinical setting therefore appears to be well justified.