title: 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.affiliation: Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Yu-Chen
authors.initials: YC
authors.lastname: Lee
authors.affiliation: Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Song-Chang
authors.initials: SC
authors.lastname: Lin
authors.affiliation: Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Guoyu
authors.initials: G
authors.lastname: Yu
authors.affiliation: Department of Pathology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan. Department of Pathology, Taipei Medical University Hospital, Taipei, Taiwan.
authors.forename: Chien-Jui
authors.initials: CJ
authors.lastname: Cheng
authors.affiliation: Department of Genetics, Center for Cancer Genetics and Genomics, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Bin
authors.initials: B
authors.lastname: Liu
authors.affiliation: Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Hsuan-Chen
authors.initials: HC
authors.lastname: Liu
authors.affiliation: Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: David H
authors.initials: DH
authors.lastname: Hawke
authors.affiliation: Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Nila U
authors.initials: NU
authors.lastname: Parikh
authors.affiliation: Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Andreas
authors.initials: A
authors.lastname: Varkaris
authors.affiliation: Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Paul
authors.initials: P
authors.lastname: Corn
authors.affiliation: Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Christopher
authors.initials: C
authors.lastname: Logothetis
authors.affiliation: Department of Orthopedic Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Robert L
authors.initials: RL
authors.lastname: Satcher
authors.affiliation: Department of Medicine, Baylor College of Medicine, Houston, Texas.
authors.forename: Li-Yuan
authors.initials: LY
authors.lastname: Yu-Lee
authors.affiliation: Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. slin@mdanderson.org ggallick@mdanderson.org.
authors.forename: Gary E
authors.initials: GE
authors.lastname: Gallick
authors.affiliation: Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas. Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. slin@mdanderson.org ggallick@mdanderson.org.
authors.forename: Sue-Hwa
authors.initials: SH
authors.lastname: Lin
mesh_terms: D000813:Anilides / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D001842:Bone and Bones / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000502:physiology*; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D009999:Ossification, Heterotopic / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000473:pathology*; D011725:Pyridines / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D023041:Xenograft Model Antitumor Assays
chemical_list: D000813:Anilides; D000970:Antineoplastic Agents; D011725:Pyridines; C558660:cabozantinib