Login to Access Video or Poster Abstract: MP99-10
Sources of Funding: NIH R01 CA136664 (C.S.S.), NIH R01 CA130916 (M.D.H.), NIH P30 CA086862 (University of Iowa Holden Comprehensive Cancer Center), Andersen-Hebbeln Prostate Cancer Research Fund

Introduction

Integrin α3β1, a major receptor for laminin isoforms in the prostate epithelial basal lamina, is frequently downregulated in prostate cancer. We have uncovered an α3β1-Abl kinase-Hippo signaling axis that functions to suppress prostate cancer progression and metastasis. Disrupting this pathway by depleting α3 integrin or treating with the Abl kinase inhibitor, imatinib, unleash an aggressive, metastatic phenotype in a pre-clinical model of castrate-resistant prostate cancer (CRPC). Here, our objective was to elucidate the specific contributions of the two Abl kinases, Abl1 and Arg/Abl2 to suppressing a metastatic phenotype, and investigate an Abl-targeted therapeutic, GNF-5, which does not also cross-inhibit the PDGF receptor or c-Kit._x000D_

Methods

We used a combination of genetic and pharmacological approaches to interfere with α3 integrin and Abl kinase activity in CRPC cells and examined the effects on metastasis in vivo and in vitro assays of malignant behavior.

Results

Loss of α3 integrin promoted progression and metastasis in vivo and low anchorage 3D growth, migration and invasion in vitro. These phenotypes were linked to disruptions in a signaling pathway leading from α3 integrin through Abl kinases to limit the activity of YAP and WWTR1/TAZ, the transcriptional coactivators that are the targets of the Hippo suppressor pathway. The highly specific, allosteric Abl kinase inhibitor, GNF-5, and imatinib, produced essentially identical increases in 3D growth, phenocopying the loss of α3 integrin. Depleting either Abl1 or Abl2 by RNAi promoted 3D growth and migration, and depleting both kinases simultaneously produced synergistic effects, dramatically increasing both growth in 3D and cell migration.

Conclusions

The presence of a novel α3β1-Abl kinase-Hippo suppressor pathway in prostate cancer suggests new potential strategies for targeting integrin signaling pathways in prostate cancer and may help to explain the failure of imatinib in prostate cancer clinical trials.

Funding

NIH R01 CA136664 (C.S.S.), NIH R01 CA130916 (M.D.H.), NIH P30 CA086862 (University of Iowa Holden Comprehensive Cancer Center), Andersen-Hebbeln Prostate Cancer Research Fund