Therapies that target
cancer cells may have unexpected effects on the tumor microenvironment that affects
therapy outcomes or render
therapy resistance.
Prostate cancer (PCa) bone
metastasis is uniquely associated with osteoblastic bone lesions and treatment with
cabozantinib, a
VEGFR-2 and MET inhibitor, leads to a reduction in number and/or intensity of lesions on bone scans. However, resistance to
cabozantinib therapy inevitably occurs. We examined the effect of
cabozantinib on osteoblast differentiation and secretion in the context of
therapy resistance. We showed that primary mouse osteoblasts express VEGFR2 and MET and
cabozantinib treatment decreased osteoblast proliferation but enhanced their differentiation. A genome-wide analysis of transcriptional responses of osteoblasts to
cabozantinib identified a set of genes accounting for inhibition of proliferation and stimulation of differentiation, and a spectrum of secreted
proteins induced by
cabozantinib, including pappalysin, IGFBP2, WNT 16, and DKK1. We determined that these
proteins were upregulated in the
conditioned medium of
cabozantinib-treated osteoblasts (CBZ-CM) compared to control CM. Treatment of C4-2B4 or PC3-mm2 PCa cells with CBZ-CM increased the anchorage-independent growth and migration of these PCa cells compared to cells treated with control CM. These results suggest that the effect of
cabozantinib on the tumor microenvironment may increase
tumor cell survival and cause
therapy resistance.