Resistance to currently available targeted therapies significantly hampers the 
survival of patients with prostate cancer with bone metastasis. Here we 
demonstrate an important resistance mechanism initiated from tumor-induced bone. 
Studies using an osteogenic patient-derived xenograft, MDA-PCa-118b, revealed 
that tumor cells resistant to cabozantinib, a Met and VEGFR-2 inhibitor, reside 
in a "resistance niche" adjacent to prostate cancer-induced bone. We performed 
secretome analysis of the conditioned medium from tumor-induced bone to identify 
proteins (termed "osteocrines") found within this resistance niche. In 
accordance with previous reports demonstrating that activation of integrin 
signaling pathways confers therapeutic resistance, 27 of the 90 osteocrines 
identified were integrin ligands. We found that following cabozantinib 
treatment, only tumor cells positioned adjacent to the newly formed woven bone 
remained viable and expressed high levels of pFAK-Y397 and pTalin-S425, 
mediators of integrin signaling. Accordingly, treatment of C4-2B4 cells with 
integrin ligands resulted in increased pFAK-Y397 expression and cell survival, 
whereas targeting integrins with FAK inhibitors PF-562271 or defactinib 
inhibited FAK phosphorylation and reduced the survival of PC3-mm2 cells. 
Moreover, treatment of MDA-PCa-118b tumors with PF-562271 led to decreased tumor 
growth, irrespective of initial tumor size. Finally, we show that upon treatment 
cessation, the combination of PF-562271 and cabozantinib delayed tumor 
recurrence in contrast to cabozantinib treatment alone. Our studies suggest that 
identifying paracrine de novo resistance mechanisms may significantly contribute 
to the generation of a broader set of potent therapeutic tools that act 
combinatorially to inhibit metastatic prostate cancer.