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 co

SUBMITTER: Bhattacharya B 

PROVIDER: S-EPMC5045388 | biostudies-literature | 2016 May

REPOSITORIES: biostudies-literature