Reference Detail

Ref Type Journal Article
PMID (27659046)
Authors Horn T, Ferretti S, Ebel N, Tam A, Ho S, Harbinski F, Farsidjani A, Zubrowski M, Sellers WR, Schlegel R, Porter D, Morris E, Wuerthner J, Jeay S, Greshock J, Halilovic E, Garraway LA, Caponigro G, Lehár J
Title High-Order Drug Combinations Are Required to Effectively Kill Colorectal Cancer Cells.
Journal Cancer research
Vol 76
Issue 23
Date 2016 Dec 01
URL
Abstract Text 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.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
KRAS mutant TP53 mutant colorectal cancer sensitive Alpelisib + Erlotinib + Navitoclax + Trametinib Preclinical - Cell culture Actionable In a preclinical study, the combination of Navitoclax (ABT-263), Mekinist (trametinib), Alpelisib (BYL719), and Tarceva (erlotinib) resulted in the greatest synergistic effect and inhibition of cell growth in colorectal cancer cells harboring a KRAS mutation and TP53 mutation compared to the double or triple combinations of the therapies (PMID: 27659046). 27659046
BRAF mut TP53 mut colorectal cancer sensitive Alpelisib + Dabrafenib + Erlotinib + Navitoclax Preclinical - Cell culture Actionable In a preclinical study, the combination of Navitoclax (ABT-263), Alpelisib (BYL719), Tafinlar (dabrafenib), and Tarceva (erlotinib) resulted in the greatest synergistic effect and inhibition of cell growth in colorectal cancer cells harboring a BRAF mutation and TP53 mutation in culture compared to the double or triple combinations of the therapies (PMID: 27659046). 27659046
KRAS mut + TP53 wild-type colorectal cancer sensitive Alpelisib + CGM097 + Navitoclax + Trametinib Preclinical - Cell culture Actionable In a preclinical study, the combination of Navitoclax (ABT-263), Alpelisib (BYL719), Mekinist (trametinib), and CGM097 resulted in the greatest synergistic effect and inhibition of cell growth in colorectal cancer cells harboring a KRAS mutation and wild-type TP53 in culture compared to the double or triple combinations of the therapies (PMID: 27659046). 27659046
BRAF mut + TP53 wild-type colorectal cancer sensitive CGM097 + Dabrafenib + Navitoclax + PF-04217903 Preclinical - Cell culture Actionable In a preclinical study, the combination of Navitoclax (ABT-263), CGM097, Tafinlar (dabrafenib), and PF04217903 resulted in the greatest synergistic effect and inhibition of cell growth in colorectal cancer cells harboring a BRAF mutation and wild-type TP53 in culture compared to the double or triple combinations of the therapies (PMID: 27659046). 27659046