title: High-Order Drug Combinations Are Required to Effectively Kill Colorectal Cancer Cells.
abstract: Like classical chemotherapy regimens used to treat cancer, targeted therapies will also rely upon polypharmacology, but tools are still lacking to predict which combinations of molecularly targeted drugs may be most efficacious. In this study, we used image-based proliferation and apoptosis assays in colorectal cancer cell lines to systematically investigate the efficacy of combinations of two to six drugs that target critical oncogenic pathways. Drug pairs targeting key signaling pathways resulted in synergies across a broad spectrum of genetic backgrounds but often yielded only cytostatic responses. Enhanced cytotoxicity was observed when additional processes including apoptosis and cell cycle were targeted as part of the combination. In some cases, where cell lines were resistant to paired and tripled drugs, increased expression of antiapoptotic proteins was observed, requiring a fourth-order combination to induce cytotoxicity. Our results illustrate how high-order drug combinations are needed to kill drug-resistant cancer cells, and they also show how systematic drug combination screening together with a molecular understanding of drug responses may help define optimal cocktails to overcome aggressive cancers. Cancer Res; 76(23); 6950-63. ©2016 AACR.
authors.affiliation: Translational Clinical Oncology, Novartis Institutes for Biomedical Research, Cambridge, Massachusetts.
authors.forename: Thomas
authors.initials: T
authors.lastname: Horn
authors.affiliation: Oncology Disease Area, Novartis Institutes for Biomedical Research, Basel, Switzerland.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Ferretti
authors.affiliation: Oncology Disease Area, Novartis Institutes for Biomedical Research, Basel, Switzerland.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Ebel
authors.affiliation: Translational Clinical Oncology, Novartis Institutes for Biomedical Research, Cambridge, Massachusetts.
authors.forename: Angela
authors.initials: A
authors.lastname: Tam
authors.affiliation: Oncology Disease Area, Novartis Institutes for Biomedical Research, Cambridge, Massachusetts.
authors.forename: Samuel
authors.initials: S
authors.lastname: Ho
authors.affiliation: Developmental and Molecular Pathways, Novartis Institutes for Biomedical Research, Cambridge, Massachusetts.
authors.forename: Fred
authors.initials: F
authors.lastname: Harbinski
authors.affiliation: Oncology Disease Area, Novartis Institutes for Biomedical Research, Cambridge, Massachusetts.
authors.forename: Ali
authors.initials: A
authors.lastname: Farsidjani
authors.affiliation: Translational Clinical Oncology, Novartis Institutes for Biomedical Research, Cambridge, Massachusetts.
authors.forename: Matthew
authors.initials: M
authors.lastname: Zubrowski
authors.affiliation: Oncology Disease Area, Novartis Institutes for Biomedical Research, Cambridge, Massachusetts.
authors.forename: William R
authors.initials: WR
authors.lastname: Sellers
authors.affiliation: Translational Clinical Oncology, Novartis Institutes for Biomedical Research, Cambridge, Massachusetts.
authors.forename: Robert
authors.initials: R
authors.lastname: Schlegel
authors.affiliation: Translational Clinical Oncology, Novartis Institutes for Biomedical Research, Cambridge, Massachusetts.
authors.forename: Dale
authors.initials: D
authors.lastname: Porter
authors.affiliation: Translational Clinical Oncology, Novartis Institutes for Biomedical Research, Cambridge, Massachusetts.
authors.forename: Erick
authors.initials: E
authors.lastname: Morris
authors.affiliation: Oncology Disease Area, Novartis Institutes for Biomedical Research, Basel, Switzerland.
authors.forename: Jens
authors.initials: J
authors.lastname: Wuerthner
authors.affiliation: Oncology Disease Area, Novartis Institutes for Biomedical Research, Basel, Switzerland.
authors.forename: Sébastien
authors.initials: S
authors.lastname: Jeay
authors.affiliation: Translational Clinical Oncology, Novartis Institutes for Biomedical Research, Cambridge, Massachusetts.
authors.forename: Joel
authors.initials: J
authors.lastname: Greshock
authors.affiliation: Translational Clinical Oncology, Novartis Institutes for Biomedical Research, Cambridge, Massachusetts.
authors.forename: Ensar
authors.initials: E
authors.lastname: Halilovic
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute/Harvard Medical School, Boston, Massachusetts.
authors.forename: Levi A
authors.initials: LA
authors.lastname: Garraway
authors.affiliation: Translational Clinical Oncology, Novartis Institutes for Biomedical Research, Cambridge, Massachusetts. giordano.caponigro@novartis.com lehar@google.com.
authors.forename: Giordano
authors.initials: G
authors.lastname: Caponigro
authors.affiliation: Translational Clinical Oncology, Novartis Institutes for Biomedical Research, Cambridge, Massachusetts. giordano.caponigro@novartis.com lehar@google.com.
authors.forename: Joseph
authors.initials: J
authors.lastname: Lehár
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D049109:Cell Proliferation; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics; D005260:Female; D006801:Humans; D051379:Mice; D015398:Signal Transduction