Acquired resistance to combination treatment through loss of synergy with MEK and PI3K inhibitors in colorectal cancer

作者：Bhattacharya Bhaskar^*; Low Sarah Hong Hui; Chong Mei Ling; Chia Dilys; Koh King Xin; Sapari Nur Sabrina; Kaye Stanley; Huynh Hung; Benoukraf Touati; Soong Richie^*

来源：Oncotarget, 2016, 7(20): 29187-29198.

DOI：10.18632/oncotarget.8692

• acquired resistance
• combination therapy
• MEK inhibitors
• PI3K inhibitors
• synergy

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.

• 出版日期2016-5-17