Identification of Bone-Derived Factors Conferring De Novo Therapeutic Resistance in Metastatic Prostate Cancer.

Abstract

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.

• Authors: Yu-Chen Lee, Song-Chang Lin, Guoyu Yu, Chien-Jui Cheng, Bin Liu, Hsuan-Chen Liu, David H Hawke, Nila U Parikh, Andreas Varkaris, Paul Corn, Christopher Logothetis, Robert L Satcher, Li-Yuan Yu-Lee, Gary E Gallick, Sue-Hwa Lin
• Journal: Cancer research (Cancer Res) Vol. 75 Issue 22 Pg. 4949-59 (Nov 15 2015) ISSN: 1538-7445 [Electronic] United States
• PMID: 26530902 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: ©2015 American Association for Cancer Research.

Chemical References

• Anilides
• Antineoplastic Agents
• Pyridines
• cabozantinib

Topics

• Anilides (pharmacology)
• Animals
• Antineoplastic Agents (pharmacology)
• Bone and Bones (metabolism)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Drug Resistance, Neoplasm (physiology)
• Humans
• Immunohistochemistry
• Male
• Mice
• Ossification, Heterotopic (metabolism)
• Prostatic Neoplasms (pathology)
• Pyridines (pharmacology)
• Reverse Transcriptase Polymerase Chain Reaction
• Xenograft Model Antitumor Assays