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

Haagensen, Emma J.; Thomas, Huw D.; Mudd, Clare; Tsonou, Elpida; Wiggins, Ceri M.; Maxwell, Ross J.; Moore, Jonathan D.; Newell, David R.

doi:10.1016/j.ejca.2015.12.012

Cited by 14 publications

(15 citation statements)

References 32 publications

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“…In our study, KRAS did not change cancer cell characteristics in 2D culture; however, it dramatically altered characteristics in 3D culture, consistent with the results of previous studies [ 21 , 47 ]. ID8 cells formed few spheroid structures and could not proliferate without growth factor stimulation or interactions with TME [ 18 ].…”

Section: Discussionsupporting

confidence: 93%

“…Others have demonstrated that mitochondrial metabolism and mitochondrial reactive oxygen species generation are essential for KRAS-induced cell proliferation and tumorigenesis [ 20 ]. Similarly, KRAS is expected to be closely related to anchorage-independent cancer cell growth in colorectal cancer cell lines [ 21 ]. In this study, we assessed the role of the KRAS oncogene in ovarian cancer cell dissemination, focusing on the stability of cells in spheroid condition, as well as the modulation of intracellular signaling following spheroid transformation.…”

Section: Introductionmentioning

confidence: 99%

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The oncogene KRAS promotes cancer cell dissemination by stabilizing spheroid formation via the MEK pathway

et al. 2018

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BackgroundPeritoneal dissemination is a critical prognostic factor in ovarian cancer. Although stabilized spheroid formation promotes cancer cell peritoneal dissemination in ovarian cancer, the associated oncogenes are unknown. In this study, we assessed the role of the KRAS oncogene in ovarian cancer cell dissemination, focusing on the stability of cells in spheroid condition, as well as the modulation of intracellular signaling following spheroid transformation.MethodsWe used ID8, a murine ovarian cancer cell line, and ID8-KRAS, an oncogenic KRAS (G12 V)-transduced ID8 cell line in this study. Spheroid-forming (3D) culture and cell proliferation assays were performed to evaluate the growth characteristics of these cells. cDNA microarray analysis was performed to identify genes involved in KRAS-associated signal transduction in floating condition. A MEK inhibitor was used to evaluate the effect on cancer peritoneal dissemination.ResultsCell viability and proliferation in monolayer (2D) cultures did not differ between ID8 and ID8-KRAS cells. However, the proportions of viable and proliferating ID8-KRAS cells in 3D culture were approximately 2-fold and 5-fold higher than that of ID8, respectively. Spheroid-formation was increased in ID8-KRAS cells. Analysis of peritoneal floating cells obtained from mice intra-peritoneally injected with cancer cells revealed that the proportion of proliferating cancer cells was approximately 2-fold higher with ID8-KRAS than with ID8 cells. Comprehensive cDNA microarray analysis revealed that pathways related to cell proliferation, and cell cycle checkpoint and regulation were upregulated specifically in ID8-KRAS cells in 3D culture, and that some genes partially regulated by the MEK-ERK pathway were upregulated only in ID8-KRAS cells in 3D culture. Furthermore, a MEK inhibitor, trametinib, suppressed spheroid formation in 3D culture of ID8-KRAS cells, although trametinib did not affect 2D-culture cell proliferation. Finally, we demonstrated that trametinib dramatically improved the prognosis for mice with ID8-KRAS tumors in an in vivo mouse model.ConclusionsOur data indicated that KRAS promoted ovarian cancer dissemination by stabilizing spheroid formation and that the MEK pathway is important for stabilized spheroid formation. Disruption of spheroid formation by a MEK inhibitor could be a therapeutic target for cancer peritoneal dissemination.Electronic supplementary materialThe online version of this article (10.1186/s12885-018-4922-4) contains supplementary material, which is available to authorized users.

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Section: Discussionsupporting

confidence: 93%

Section: Introductionmentioning

confidence: 99%

The oncogene KRAS promotes cancer cell dissemination by stabilizing spheroid formation via the MEK pathway

et al. 2018

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“…The degree of synergy with the WX-037 and WX-554 combination was consistent with in vitro published studies using combinations of other PI3K and MEK inhibitors [2, 18, 23, 24, 32, 33]. …”

Section: Discussionsupporting

confidence: 85%

Enhanced anti-tumour activity of the combination of the novel MEK inhibitor WX-554 and the novel PI3K inhibitor WX-037

Haagensen

Thomas

Schmalix

et al. 2016

Cancer Chemother Pharmacol

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PurposeTumours frequently have defects in multiple oncogenic pathways, e.g. MAPK and PI3K signalling pathways, and combinations of targeted therapies may be required for optimal activity. This study evaluated the novel MEK inhibitor WX-554 and the novel PI3K inhibitor WX-037, as single agents and in combination, in colorectal carcinoma cell lines and tumour xenograft-bearing mice.MethodsIn vitro growth inhibition, survival and signal transduction were measured using the Sulforhodamine B, clonogenic and Western blotting assays, respectively, in HCT116 and HT29 cell lines. In vivo anti-tumour efficacy and pharmacokinetic properties were assessed in HCT116 and HT29 human colorectal cancer xenograft tumour-bearing mice.ResultsThe combination of WX-554 and WX-037 exhibited marked synergistic growth inhibition in vitro, which was associated with increased cytotoxicity and enhanced inhibition of ERK and S6 phosphorylation, compared to either agent alone. Pharmacokinetic analyses indicated that there was no PK interaction between the two drugs at low doses, but that at higher doses, WX-037 may delay the tumour uptake of WX-554. In vivo efficacy studies revealed that the combination of WX-037 and WX-554 was non-toxic and exhibited marked tumour growth inhibition greater than observed with either agent alone.ConclusionThese studies show for the first time that combination treatment with the novel MEK inhibitor WX-554 and the novel PI3K inhibitor WX-037 can induce synergistic growth inhibition in vitro, which translates into enhanced anti-tumour efficacy in vivo.Electronic supplementary materialThe online version of this article (doi:10.1007/s00280-016-3186-4) contains supplementary material, which is available to authorized users.

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“…The c-mos proto-oncogene was one of the first proto-oncogenes to be cloned [1] . Apart from its role in meiosis, many efforts have been made to illuminate the mechanisms by which c-mos might acts as an oncogene [2] , [3] , [4] , [5] , [6] , [7] , [8] , [9] , [10] . c-mos or its coding messenger RNA have been confirmed in most somatic tissues at low levels.…”

Section: Datamentioning

confidence: 99%

Data on tumor progression of c-mos deficiency in murine models of Kras lung and Apc colorectal cancer

et al. 2018

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The c-mos proto-oncogene was one of the first proto-oncogenes to be cloned. Apart from its role in meiosis, many efforts have been made to illuminate the mechanisms by which c-mos might acts as an oncogene. Increased Mos expression was found in most human tumor tissues. However, a detailed role of c-mos in tumor progression remains unknown.In this study, we analyzed online databases to find out the correlation between Mos expression and poor survival rates in human cancer patients. Then, we crossed c-mos knockout mice with ApcMin or KrasG12D mice to generate intestinal cancer model and lung cancer model, respectively. Tumor progression was monitored, and the influence of c-mos deficiency on cancer formation was investigated.

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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

Cited by 14 publications

References 32 publications

The oncogene KRAS promotes cancer cell dissemination by stabilizing spheroid formation via the MEK pathway

The oncogene KRAS promotes cancer cell dissemination by stabilizing spheroid formation via the MEK pathway

Enhanced anti-tumour activity of the combination of the novel MEK inhibitor WX-554 and the novel PI3K inhibitor WX-037

Data on tumor progression of c-mos deficiency in murine models of Kras lung and Apc colorectal cancer

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