title: Acquired resistance to combination treatment through loss of synergy with MEK and PI3K inhibitors in colorectal cancer.
abstract: Historically, understanding of acquired resistance (AQR) to combination treatment has been based on knowledge of resistance to its component agents. To test whether an altered drug interaction could be an additional factor in AQR to combination treatment, models of AQR to combination and single agent MEK and PI3K inhibitor treatment were generated. Combination indices indicated combination treatment of PI3K and MEK inhibitors remained synergistic in cells with AQR to single agent but not combination AQR cells. Differences were also observed between the models in cellular phenotypes, pathway signaling and drug cross-resistance. Genomics implicated TGFB2-EDN1 overexpression as candidate determinants in models of AQR to combination treatment. Supplementation of endothelin in parental cells converted synergism to antagonism. Silencing of TGFB2 or EDN1 in cells with AQR conferred synergy between PI3K and MEK inhibitor. These results highlight that AQR to combination treatment may develop through alternative mechanisms to those of single agent treatment, including a change in drug interaction.
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, Singapore.
authors.forename: Bhaskar
authors.initials: B
authors.lastname: Bhattacharya
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, Singapore.
authors.forename: Sarah Hong Hui
authors.initials: SH
authors.lastname: Low
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, Singapore.
authors.forename: Mei Ling
authors.initials: ML
authors.lastname: Chong
authors.affiliation: Department of Pharmacy, National University of Singapore, Singapore.
authors.forename: Dilys
authors.initials: D
authors.lastname: Chia
authors.affiliation: Department of Pathology, National University of Singapore, Singapore.
authors.forename: King Xin
authors.initials: KX
authors.lastname: Koh
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, Singapore.
authors.forename: Nur Sabrina
authors.initials: NS
authors.lastname: Sapari
authors.affiliation: Drug Development Unit, Royal Marsden NHS Trust, The Royal Marsden NHS Foundation Trust, London, United Kingdom.
authors.forename: Stanley
authors.initials: S
authors.lastname: Kaye
authors.affiliation: Laboratory of Molecular Endocrinology, National Cancer Centre of Singapore, Singapore.
authors.forename: Huynh
authors.initials: H
authors.lastname: Hung
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, Singapore.
authors.forename: Touati
authors.initials: T
authors.lastname: Benoukraf
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, Singapore.|Department of Pathology, National University of Singapore, Singapore.
authors.forename: Richie
authors.initials: R
authors.lastname: Soong
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000473:pathology*; D019008:Drug Resistance, Neoplasm / Q000502:physiology*; D004357:Drug Synergism; D045325:HCT116 Cells; D006801:Humans; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors*; D051379:Mice; D016513:Mice, SCID; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
chemical_list: D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D020930:MAP Kinase Kinase Kinases
keywords: MEK inhibitors; PI3K inhibitors; acquired resistance; combination therapy; synergy