Targeting JAG1 Sensitizes Bone Metastases to Chemotherapy

Bone metastasis occurs in the majority of patients with late-stage breast cancer. The bone-forming osteoblast cells are essential for creating an osteogenic niche that allows for the survival and colonization of disseminated tumor cells in the bone. Expression of the Notch ligands jagged1 (JAG1) and NOTCH1 on breast cancer cells is associated with a poor prognosis, and JAG1 has been shown to promote bone metastasis by activating Notch signaling in osteoblasts and osteoclasts. However, attempts to target Notch signaling with γ-secretase inhibitors caused severe toxicity, preventing their further clinical development to treat bone metastasis. Zheng, Bae, and colleagues developed a fully humanized monoclonal antibody against JAG1 (15D11) to potentially limit the toxicity of Notch inhibition by targeting a single Notch ligand. 15D11 effectively blocked JAG1 and downstream Notch signaling with minimal toxicity in vivo. In a breast cancer bone metastasis xenograft model, 15D11 suppressed bone metastasis of JAG1-expressing tumor cells and synergized with chemotherapy to further reduce bone metastases. Mechanistically, chemotherapy induced JAG1 expression in osteoblastic cells (via induction of reactive oxygen species), which promoted the seeding and outgrowth of metastatic tumor cells in the bone. Coculturing tumor cells with osteoblasts protected against chemotherapy-induced apoptosis, and this chemoprotection could be reversed by 15D11. Interactions with osteoblast lineage cells protected JAG1-expressing tumor cells in the bone from chemotherapy, inducing chemoresistance. Thus, targeting JAG1 sensitized bone metastases to chemotherapy. In a mouse model of breast cancer with spontaneous bone metastasis, 15D11 treatment reduced the incidence of bone metastases in combination with chemotherapy. Consistent with these findings, in patients with breast cancer JAG1 was initially expressed at low levels on osteoblasts and upregulated following chemotherapy. Altogether, these findings suggest that JAG1 targeting may be beneficial in preventing and treating breast cancer bone metastases in combination with chemotherapy. Further, the safety profile of the anti-JAG1 antibody 15D11 supports its further clinical development.

Zheng H, Bae Y, Kasimir-Bauer S, Tang R, Chen J, Ren G, et al. Therapeutic antibody targeting tumor- and osteoblastic niche-derived jagged1 sensitizes bone metastasis to chemotherapy. Cancer Cell 2017;32:731–47.

• ©2017 American Association for Cancer Research.