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Acquired Resistance to Combination Treatment through Loss of Synergy with MEK and PI3K Inhibitors in Colorectal Cancer. (Oncotarget, Apr 2016)

Bhattacharya B1, Hui Low SH1, Chong ML1, Chia D2, Koh KX3, Sapari NS1, Kaye S4, Hung H5, Benoukraf T1, Soong R1,3

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.

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.

PMID: 27081080