The Impact of Genetics on CRC Therapy: From Adaptive Mutability to Drug Resistance

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Cover image for research topic "The Impact of Genetics on CRC Therapy: From Adaptive Mutability to Drug Resistance"
Editors
2
Giovanni Crisafulli
IFOM - The FIRC Institute of Molecular Oncology
Giulia Siravegna
Harvard Medical School
Impact
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Original Research
30 May 2022
RKO Control*1, and APCmut*2 cells were plated in 96-well plates and treated with vehicle (0.01% DMSO) or the compound library (average compound concentration of the library in media was 10µM). After 4 days incubation with the drug library, cell viability was assessed. Z-scores were compared to identify compounds that cause selective loss of viability in APC mutated cells, in comparison to wt APC cells. Graphs represent Z-scores for (A) mevastatin and (B) lovastatin for each of the three replicate drug screens. RKO Control*1, Control*2, APCmut*1 and APCmut*2 cells were treated with increasing concentrations of (C) lovastatin (0, 2 µM, 4 µM, 6 µM, 8 µM & 10 µM), (D) mevastatin (0, 2 µM, 4 µM, 6 µM, 8 µM & 10 µM) and (E) simvastatin (0, 1 µM, 2 µM, 3 µM & 4 µM). After 4 days treatment, cell viability was measured using an ATP-based luminescence assay. In vivo efficacy experiments were performed on 40 NMRI nu/nu mice injected with either APC mutant patient derived tumor cells (F) or wt APC patient derived tumor cells (G). When the tumors were measurable, mice were treated daily by gavage with 50mg/kg simvastatin or vehicle. Tumors were measured twice a week and tumor size was normalized to initial treatment measurements. (C–E) Data represent mean ± SEM of three independent experiments. *p ≤ 0.05; ****p ≤ 0.00005; ns, non-significant.
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