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Colorectal cancer spheroid biobanks: multi-level approaches to drug sensitivity studies
- Source :
- Cell Biology and Toxicology. 34:459-469
- Publication Year :
- 2018
- Publisher :
- Springer Science and Business Media LLC, 2018.
-
Abstract
- Biobanking of molecularly characterized colorectal cancer stem cells (CSCs) generated from individual patients and growing as spheroids in defined serum-free media offer a fast, feasible, and multi-level approach for the screening of targeted therapies and drug resistance molecular studies. By combining in vitro and in vivo analyses of cetuximab efficacy with genetic data on an ongoing collection of stem cell-enriched spheroids, we describe the identification and preliminary characterization of microsatellite stable (MSS) CSCs that, despite the presence of the KRAS (G12D) mutation, display epidermal growth factor (EGF)-dependent growth and are strongly inhibited by anti-EGF-receptor (EGFR) treatment. In parallel, we detected an increased resistance to anti-EGFR therapy of microsatellite instable (MSI) CSC lines irrespective of KRAS mutational status. MSI CSC lines carried mutations in genes coding for proteins with a role in RAS and calcium signaling, highlighting the role of a genomically unstable context in determining anti-EGFR resistance. Altogether, these results argue for a multifactorial origin of anti-EGFR resistance that emerges as the effect of multiple events targeting direct and indirect regulators of the EGFR pathway. An improved understanding of key molecular determinants of sensitivity/resistance to EGFR inhibition will be instrumental to optimize the clinical efficacy of anti-EGFR agents, representing a further step towards personalized treatments.
- Subjects :
- 0301 basic medicine
Colorectal cancer
Health, Toxicology and Mutagenesis
Drug Evaluation, Preclinical
Cetuximab
Antineoplastic Agents
Context (language use)
Personalized therapy
Drug resistance
Biology
Toxicology
medicine.disease_cause
Cancer stem cells
Spheroid cultures
Proto-Oncogene Proteins p21(ras)
03 medical and health sciences
Epidermal growth factor
Cancer stem cell
Spheroids, Cellular
Tumor Cells, Cultured
medicine
Humans
Panitumumab
Precision Medicine
Biological Specimen Banks
Epidermal Growth Factor
Antibodies, Monoclonal
Cell Biology
medicine.disease
ErbB Receptors
030104 developmental biology
Drug Resistance, Neoplasm
Mutation
Neoplastic Stem Cells
Cancer research
KRAS
Colorectal Neoplasms
medicine.drug
Subjects
Details
- ISSN :
- 15736822 and 07422091
- Volume :
- 34
- Database :
- OpenAIRE
- Journal :
- Cell Biology and Toxicology
- Accession number :
- edsair.doi.dedup.....6bcf65631ccde40ec5208c665228608d