title: 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.
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.
authors.affiliation: Newcastle Cancer Centre, Northern Institute for Cancer Research, Paul O'Gorman Building, Medical School, Newcastle University, Framlington Place, Newcastle-upon-Tyne, NE2 4HH, UK.
authors.forename: Emma J
authors.initials: EJ
authors.lastname: Haagensen
authors.affiliation: Newcastle Cancer Centre, Northern Institute for Cancer Research, Paul O'Gorman Building, Medical School, Newcastle University, Framlington Place, Newcastle-upon-Tyne, NE2 4HH, UK.
authors.forename: Huw D
authors.initials: HD
authors.lastname: Thomas
authors.affiliation: Horizon Discovery, 7100 Cambridge Research Park, Cambridge, CB25 9TL, UK.
authors.forename: Clare
authors.initials: C
authors.lastname: Mudd
authors.affiliation: Horizon Discovery, 7100 Cambridge Research Park, Cambridge, CB25 9TL, UK.
authors.forename: Elpida
authors.initials: E
authors.lastname: Tsonou
authors.affiliation: Horizon Discovery, 7100 Cambridge Research Park, Cambridge, CB25 9TL, UK.
authors.forename: Ceri M
authors.initials: CM
authors.lastname: Wiggins
authors.affiliation: Newcastle Cancer Centre, Northern Institute for Cancer Research, Paul O'Gorman Building, Medical School, Newcastle University, Framlington Place, Newcastle-upon-Tyne, NE2 4HH, UK.
authors.forename: Ross J
authors.initials: RJ
authors.lastname: Maxwell
authors.affiliation: Horizon Discovery, 7100 Cambridge Research Park, Cambridge, CB25 9TL, UK.
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Moore
authors.affiliation: Newcastle Cancer Centre, Northern Institute for Cancer Research, Paul O'Gorman Building, Medical School, Newcastle University, Framlington Place, Newcastle-upon-Tyne, NE2 4HH, UK. Electronic address: herbie.newell@ncl.ac.uk.
authors.forename: David R
authors.initials: DR
authors.lastname: Newell
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D014408:Biomarkers, Tumor / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D058534:Class I Phosphatidylinositol 3-Kinases; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008819:Mice, Nude; D009154:Mutation; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics* / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics*; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D013997:Time Factors; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D058534:Class I Phosphatidylinositol 3-Kinases; D020930:MAP Kinase Kinase Kinases; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D016283:Proto-Oncogene Proteins p21(ras); D058570:TOR Serine-Threonine Kinases; C117307:KRAS protein, human; C546842:MTOR protein, human; C484760:PIK3CA protein, human
keywords: Biomarker; Combination; Isogenic; MEK; PI3K