title: Mechanistic Support for Combined MET and AR Blockade in Castration-Resistant Prostate Cancer.
abstract: A recent phase III trial of the MET kinase inhibitor cabozantinib in men with castration-resistant prostate cancer (CRPC) failed to meet its primary survival end point; however, most men with CRPC have intact androgen receptor (AR) signaling. As previous work supports negative regulation of MET by AR signaling, we hypothesized that intact AR signaling may have limited the efficacy of cabozantinib in some of these patients. To assess the role of AR signaling on MET inhibition, we first performed an in silico analysis of human CRPC tissue samples stratified by AR signaling status ((+) or (-)), which identified MET expression as markedly increased in AR(-) samples. In vitro, AR signaling inhibition in AR(+) CRPC models increased MET expression and resulted in susceptibility to ligand (HGF) activation. Likewise, MET inhibition was only effective in blocking cancer phenotypes in cells with MET overexpression. Using multiple AR(+) CRPC in vitro and in vivo models, we showed that combined cabozantinib and enzalutamide (AR antagonist) treatment was more efficacious than either inhibitor alone. These data provide a compelling rationale to combine AR and MET inhibition in CRPC and may explain the negative results of the phase III cabozantinib study in CRPC. Similarly, the expression of MET in AR(-) disease, whether due to AR inhibition or loss of AR signaling, suggests potential utility for MET inhibition in select patients with AR therapy resistance and in AR(-) prostate cancer.
authors.affiliation: Michigan Center for Translational Pathology; Department of Pathology; Comprehensive Cancer Center.
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Qiao
authors.affiliation: Michigan Center for Translational Pathology; Department of Radiation Oncology; Comprehensive Cancer Center.
authors.forename: Felix Y
authors.initials: FY
authors.lastname: Feng
authors.affiliation: Department of Urology.
authors.forename: Yugang
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Michigan Center for Translational Pathology; Howard Hughes Medical Institute.
authors.forename: Xuhong
authors.initials: X
authors.lastname: Cao
authors.affiliation: Department of Radiation Oncology.
authors.forename: Sumin
authors.initials: S
authors.lastname: Han
authors.affiliation: Department of Radiation Oncology.
authors.forename: Kari
authors.initials: K
authors.lastname: Wilder-Romans
authors.affiliation: Department of Genitourinary Medical Oncology; David H. Koch Center for Applied Research of Genitourinary Cancers.
authors.forename: Nora M
authors.initials: NM
authors.lastname: Navone
authors.affiliation: Department of Genitourinary Medical Oncology; David H. Koch Center for Applied Research of Genitourinary Cancers.
authors.forename: Christopher
authors.initials: C
authors.lastname: Logothetis
authors.affiliation: Department of Periodontics and Oral Medicine, University of Michigan School of Dentistry.
authors.forename: Russell S
authors.initials: RS
authors.lastname: Taichman
authors.affiliation: Department of Urology.
authors.forename: Evan T
authors.initials: ET
authors.lastname: Keller
authors.affiliation: Department of Urology; Comprehensive Cancer Center.
authors.forename: Ganesh S
authors.initials: GS
authors.lastname: Palapattu
authors.affiliation: Department of Internal Medicine.
authors.forename: Ajjai S
authors.initials: AS
authors.lastname: Alva
authors.affiliation: Comprehensive Cancer Center; Department of Internal Medicine.
authors.forename: David C
authors.initials: DC
authors.lastname: Smith
authors.affiliation: Michigan Center for Translational Pathology; Department of Pathology; Department of Urology; Comprehensive Cancer Center.
authors.forename: Scott A
authors.initials: SA
authors.lastname: Tomlins
authors.affiliation: Michigan Center for Translational Pathology; Department of Pathology; Department of Urology; Howard Hughes Medical Institute; Comprehensive Cancer Center. Electronic address: arul@umich.edu.
authors.forename: Arul M
authors.initials: AM
authors.lastname: Chinnaiyan
authors.affiliation: Michigan Center for Translational Pathology; Department of Urology; Comprehensive Cancer Center.
authors.forename: Todd M
authors.initials: TM
authors.lastname: Morgan
mesh_terms: D059002:Androgen Receptor Antagonists / Q000494:pharmacology*; D000813:Anilides / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001549:Benzamides; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D016000:Cluster Analysis; D004195:Disease Models, Animal; D020869:Gene Expression Profiling; D055785:Gene Knockdown Techniques; D006801:Humans; D008297:Male; D051379:Mice; D009570:Nitriles; D010669:Phenylthiohydantoin / Q000031:analogs & derivatives / Q000494:pharmacology; D064129:Prostatic Neoplasms, Castration-Resistant / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors* / Q000235:genetics; D011725:Pyridines / Q000494:pharmacology; D011944:Receptors, Androgen / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D059002:Androgen Receptor Antagonists; D000813:Anilides; D000970:Antineoplastic Agents; D001549:Benzamides; D009570:Nitriles; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D011944:Receptors, Androgen; C558660:cabozantinib; D010669:Phenylthiohydantoin; C540278:enzalutamide; D019859:Proto-Oncogene Proteins c-met