Inhibition of ROCK1 kinase modulates both tumor cells and stromal fibroblasts in pancreatic cancer.

Abstract

ROCK, or Rho-associated coiled coil-containing protein kinase, is a member of the AGC kinase family and has been shown to play a role in cell migration, ECM synthesis, stress-fiber assembly, and cell contraction. Increased ROCK expression has been reported in multiple pathological conditions, including cancer. Here, we report increased expression of ROCK 1 in pancreatic tumor epithelial cells as well as in cancer associated fibroblasts (CAF). In our analysis, 62% of tumor samples exhibited ≥2+ in staining intensity by IHC analysis, versus 40% of adjacent normal tissue samples (P<0.0001). Thus, we hypothesized that ROCKs may play a significant role in pancreatic cancer progression, and may serve as a suitable target for treatment. We report a low frequency (4/34) amplification of the ROCK1 gene locus at chromosome 18q11.1 in pancreatic ductal adenocarcinoma (PDAC) patient tissue samples by aCGH analysis. Inhibition of ROCK kinase activity by a small molecule inhibitor (fasudil) resulted in moderate (IC50s of 6-71 μM) inhibition of PDAC cell proliferation, migration, and activation of co-cultured stellate cells. In the KPC mouse model for pancreatic cancer, fasudil decreased tumor collagen deposition. This translated to an enhanced overall survival of the mice and an increase in gemcitabine uptake. Though fasudil may target both the tumor epithelial cells and the CAFs, our findings are consistent with the hypothesis that inhibition of tumor stroma enhances drug penetration and efficacy in PDAC. Overall, our data suggests that ROCK1 may serve as a potential therapeutic target to enhance current treatment regimens for pancreatic cancer.

• Authors: Clifford J Whatcott, Serina Ng, Michael T Barrett, Galen Hostetter, Daniel D Von Hoff, Haiyong Han
• Journal: PloS one (PLoS One) Vol. 12 Issue 8 Pg. e0183871 ( 2017) ISSN: 1932-6203 [Electronic] United States
• PMID: 28841710 (Publication Type: Journal Article)

Chemical References

• RNA, Small Interfering
• ROCK1 protein, human
• rho-Associated Kinases

Topics

• Animals
• Carcinoma, Pancreatic Ductal (enzymology, genetics, pathology)
• Comparative Genomic Hybridization
• Gene Silencing
• Humans
• Mice
• Neoplasm Metastasis
• Pancreatic Neoplasms (enzymology, genetics, pathology)
• RNA, Small Interfering (genetics)
• Stromal Cells (pathology)
• rho-Associated Kinases (antagonists & inhibitors, metabolism)