Control of basal-type prostate cancers with a bispecific integrin a5ß1/av antibody
Integrin a5ß1 and av crosstalk in chemotaxis and clonogenic survival of prostate cancer cells is abrogated by a bispecific a5ß1/av antibody (BsAba5ß1/av), which uniquely induces internalization and lysosomal degradation of target integrins. We hypothesized that the BsAba5ß1/av inactivates pathological mechanosignaling pathways that correlate with integrin expression from patient samples. Mechanistic studies indicate that the BsAba5ß1/av uniquely reverses YAP, beta-catenin and FAK nuclear localization compared to monospecific integrin a5ß1 and av antibody controls in basal-type androgen-receptor negative prostate cancer cells. Dual integrin av and a5 knockdown alone phenocopied the BsAba5ß1/av effect. Following BsAba5ß1/av treatment, ATAC-seq studies indicated the chromatin accessibility to TEAD and AP-1 family members was markedly reduced. In vitro and in vivo RNA-seq indicated down-regulation of Myc/E2F, TGF-beta and epithelial mesenchymal transition (EMT) and upregulation of Type I and II interferon transcriptomic pathways. The BsAba5ß1/av induced CXCL10 and CCL5 cytokine secretion, immune-infiltration of tumors, and natural-killer cell-mediated elimination of the basal-type prostate cancer xenografts in nude mice. av integrin was highly expressed and principally correlated with the Myc signaling pathway in rapid autopsy tissue microarrays, consistent with correlative data from the SU2C metastatic castration-resistant prostate cancer and DKFZ early-onset prostate cancer cohorts. These studies connect integrin signaling with the central biology of basal-type and castration-resistant prostate cancer and define a novel therapeutic strategy that controls critical immunosuppressive pathways. Overall design: RNA-seq profiling of prostate cancer cell lines and xenografts treated with BsAba5ß1/av compared to control