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Pre-clinical use of isogenic cell lines and tumours in vitro and in vivo for predictive biomarker discovery; impact of KRAS and PI3KCA mutation status on MEK inhibitor activity is model dependent

Lookup NU author(s): Dr Emma Haagensen, Huw Thomas, Dr Ross Maxwell, Professor Herbie Newell

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Abstract

Studies to identify predictive biomarkers can be carried out in isogenic cancer cell lines, which enable interrogation of the effect of a specific mutation. We assessed the effects of four drugs, the PI3K-mammalian target of rapamycin inhibitor dactolisib, the PI3K inhibitor pictrelisib, and the MEK (MAPK/ERK Kinase) inhibitors PD 0325901 and selumetinib, in isogenic DLD1 parental, KRAS(+/-), KRAS(G13D/-), PIK3CA(+/-) and PIK3CA(E545K/-) colorectal carcinoma cell lines. Importantly, we found substantial differences in the growth of these cells and in their drug sensitivity depending on whether they were studied under 2D (standard tissue culture on plastic) or 3D (in vitro soft agar and in vivo xenograft) conditions. DLD1 KRAS(+/-) and DLD1 PIK3CA(+/-) cells were more sensitive to MEK inhibitors than parental, DLD1 KRAS(G13D/-) and DLD1 PIK3CA(E545K/-) cells under 2D conditions, whereas DLD1 KRAS(G13D/-) and DLD1 PIK3CA(E545K/-) xenografts were sensitive to 10 mg/kg daily x 14 PD 0325901 in vivo (p <= 0.02) but tumours derived from parental DLD1 cells were not. These findings indicate that KRAS and PIK3CA mutations can influence the response of DLD1 colorectal cancer cell lines to MEK and PI3K inhibitors, but that the effect is dependent on the experimental model used to assess drug sensitivity. (C) 2016 Elsevier Ltd. All rights reserved.


Publication metadata

Author(s): Haagensen EJ, Thomas HD, Mudd C, Tsonou E, Wiggins CM, Maxwell RJ, Moore JD, Newell DR

Publication type: Article

Publication status: Published

Journal: European Journal of Cancer

Year: 2016

Volume: 56

Pages: 69-76

Print publication date: 01/03/2016

Online publication date: 25/01/2016

Acceptance date: 14/12/2015

ISSN (print): 0959-8049

ISSN (electronic): 1879-0852

Publisher: Elsevier

URL: http://dx.doi.org/10.1016/j.ejca.2015.12.012

DOI: 10.1016/j.ejca.2015.12.012


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