title: Resistance to Antiangiogenic Therapies by Metabolic Symbiosis in Renal Cell Carcinoma PDX Models and Patients.
abstract: Antiangiogenic drugs are used clinically for treatment of renal cell carcinoma (RCC) as a standard first-line treatment. Nevertheless, these agents primarily serve to stabilize disease, and resistance eventually develops concomitant with progression. Here, we implicate metabolic symbiosis between tumor cells distal and proximal to remaining vessels as a mechanism of resistance to antiangiogenic therapies in patient-derived RCC orthoxenograft (PDX) models and in clinical samples. This metabolic patterning is regulated by the mTOR pathway, and its inhibition effectively blocks metabolic symbiosis in PDX models. Clinically, patients treated with antiangiogenics consistently present with histologic signatures of metabolic symbiosis that are exacerbated in resistant tumors. Furthermore, the mTOR pathway is also associated in clinical samples, and its inhibition eliminates symbiotic patterning in patient samples. Overall, these data support a mechanism of resistance to antiangiogenics involving metabolic compartmentalization of tumor cells that can be inhibited by mTOR-targeted drugs.
authors.affiliation: Tumor Angiogenesis Group, ProCURE, Catalan Institute of Oncology - IDIBELL, 08908 Barcelona, Spain.
authors.forename: Gabriela
authors.initials: G
authors.lastname: Jiménez-Valerio
authors.affiliation: Tumor Angiogenesis Group, ProCURE, Catalan Institute of Oncology - IDIBELL, 08908 Barcelona, Spain.
authors.forename: Mar
authors.initials: M
authors.lastname: Martínez-Lozano
authors.affiliation: Tumor Angiogenesis Group, ProCURE, Catalan Institute of Oncology - IDIBELL, 08908 Barcelona, Spain.
authors.forename: Nicklas
authors.initials: N
authors.lastname: Bassani
authors.affiliation: Anatomopathology Service, Bellvitge University Hospital, 08907 Barcelona, Spain.
authors.forename: August
authors.initials: A
authors.lastname: Vidal
authors.affiliation: Medical Oncology Service, Catalan Institute of Oncology, 08908 Barcelona, Spain; Vall d'Hebron Institute of Oncology, Vall d'Hebron University Hospital, 08035 Barcelona, Spain.
authors.forename: María
authors.initials: M
authors.lastname: Ochoa-de-Olza
authors.affiliation: Vall d'Hebron Institute of Oncology, Vall d'Hebron University Hospital, 08035 Barcelona, Spain.
authors.forename: Cristina
authors.initials: C
authors.lastname: Suárez
authors.affiliation: Medical Oncology Service, Catalan Institute of Oncology, 08908 Barcelona, Spain.
authors.forename: Xavier
authors.initials: X
authors.lastname: García-Del-Muro
authors.affiliation: Vall d'Hebron Institute of Oncology, Vall d'Hebron University Hospital, 08035 Barcelona, Spain.
authors.forename: Joan
authors.initials: J
authors.lastname: Carles
authors.affiliation: Tumor Angiogenesis Group, ProCURE, Catalan Institute of Oncology - IDIBELL, 08908 Barcelona, Spain; Departament de Ciències Fisiològiques II, Campus de Bellvitge, Universitat de Barcelona, 08907 Barcelona, Spain.
authors.forename: Francesc
authors.initials: F
authors.lastname: Viñals
authors.affiliation: Tumor Angiogenesis Group, Bellvitge Biomedical Research Institute (IDIBELL), 08908 Barcelona, Spain.
authors.forename: Mariona
authors.initials: M
authors.lastname: Graupera
authors.affiliation: Istituto Oncologico Veneto - IRCCS, 35128 Padova, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Indraccolo
authors.affiliation: Tumor Angiogenesis Group, ProCURE, Catalan Institute of Oncology - IDIBELL, 08908 Barcelona, Spain. Electronic address: ocasanovas@iconcologia.net.
authors.forename: Oriol
authors.initials: O
authors.lastname: Casanovas
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000378:metabolism*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D000068338:Everolimus / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D007211:Indoles / Q000494:pharmacology / Q000627:therapeutic use; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000378:metabolism*; D008297:Male; D008819:Mice, Nude; D010641:Phenotype; D011758:Pyrroles / Q000494:pharmacology / Q000627:therapeutic use; D015398:Signal Transduction / Q000187:drug effects; D000077210:Sunitinib; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D020533:Angiogenesis Inhibitors; D007211:Indoles; D011758:Pyrroles; D000068338:Everolimus; D058570:TOR Serine-Threonine Kinases; D000077210:Sunitinib