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. (March 2016)

• Record Type: Journal Article
• Authors: Haagensen, Emma J.; Thomas, Huw D.; Mudd, Clare; Tsonou, Elpida; Wiggins, Ceri M.; Maxwell, Ross J.; Moore, Jonathan D.; Newell, David R.
• Is Part Of: European journal of cancer. Volume 56(2016)
• Page Start: 69
• Page End: 76
• Publication Date: 2016-03
• Subjects: MEK -- PI3K -- Combination -- Isogenic -- Biomarker; Cancer -- Periodicals; Neoplasms -- Periodicals; Cancer -- Périodiques; Cancer; Tumors; Electronic journals; Periodicals; Electronic journals; 616.994
• DOI: 10.1016/j.ejca.2015.12.012
• Languages: English
• ISSNs: 0959-8049

Abstract

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 ×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. Highlights: Isogenic cells are key models for exploring targeted anticancer drug pharmacology. The growth effect of defined genetic changes depends on in vitro & in vivo conditions. KRAS and PIK3CA impact on sensitivity to targeted agents also depends on conditions.