Acquired resistance to combination treatment through loss of synergy with MEK and PI3K inhibitors in colorectal cancer
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Bhaskar Bhattacharya1, Sarah Hong Hui Low1, Mei Ling Chong1, Dilys Chia2, King Xin Koh3, Nur Sabrina Sapari1, Stanley Kaye4, Huynh Hung5, Touati Benoukraf1, Richie Soong1,3
1Cancer Science Institute of Singapore, National University of Singapore, Singapore
2Department of Pharmacy, National University of Singapore, Singapore
3Department of Pathology, National University of Singapore, Singapore
4Drug Development Unit, Royal Marsden NHS Trust, The Royal Marsden NHS Foundation Trust, London, United Kingdom
5Laboratory of Molecular Endocrinology, National Cancer Centre of Singapore, Singapore
Richie Soong, e-mail: [email protected]
Bhaskar Bhattacharya, e-mail: [email protected]
Keywords: acquired resistance, combination therapy, MEK inhibitors, PI3K inhibitors, synergy
Received: December 01, 2015 Accepted: March 28, 2016 Published: April 11, 2016
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.
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