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Maintenance Treatment with Cetuximab and BAY86-9766 Increases Antitumor Efficacy of Irinotecan plus Cetuximab in Human Colorectal Cancer Xenograft Models
- Source :
- Clinical Cancer Research. 21:4153-4164
- Publication Year :
- 2015
- Publisher :
- American Association for Cancer Research (AACR), 2015.
-
Abstract
- Purpose: The use of cetuximab in the treatment of metastatic colorectal cancer is limited by development of resistance. Experimental Design: We have investigated in three models of highly epidermal growth factor receptor (EGFR)–dependent colorectal cancer xenografts, the effect of maintenance therapy with different kinase inhibitors alone or in combination with cetuximab, after cytotoxic treatment induction with irinotecan plus cetuximab. Results: SW48, LIM 1215, and GEO colorectal cancer cell lines were engrafted into nude mice and treated for 3 weeks with irinotecan and/or cetuximab. The combined treatment induced a significant reduction of tumor size. A subsequent experiment was performed in all three xenograft models in which after an induction treatment with irinotecan plus cetuximab, mice were randomly assigned to one of the following treatments: control, cetuximab, regorafenib, a selective PIK3CA inhibitor (PIK3CAi), a selective MEK inhibitor (MEKi), and/or the combination of each inhibitor with cetuximab. The cetuximab plus MEKi treatment determined the best antitumor activity with suppression of tumor growth. This effect was prolonged for 13 to 15 weeks after cessation of therapy and was accompanied by prolonged survival. Antitumor activity was accompanied by inhibition of the MAPK and MEK pathways. Moreover, in the cetuximab plus MEKi-treated SW48 xenograft group, KRAS mutations as a mechanism of acquired resistance were detected in 25% of cases compared with 75% KRAS mutations in the MEKi-treated group. Conclusions: A possible strategy to prevent and/or overcome resistance to anti-EGFR inhibitors in metastatic colorectal cancer is a maintenance therapy with cetuximab plus MEKi after an initial treatment with irinotecan plus cetuximab. Clin Cancer Res; 21(18); 4153–64. ©2015 AACR.
- Subjects :
- Oncology
Cancer Research
medicine.medical_specialty
Cell Survival
Class I Phosphatidylinositol 3-Kinases
MAP Kinase Signaling System
Colorectal cancer
Cetuximab
Mice, Nude
Irinotecan
medicine.disease_cause
Mice
Phosphatidylinositol 3-Kinases
chemistry.chemical_compound
Cell Line, Tumor
Regorafenib
Internal medicine
Antineoplastic Combined Chemotherapy Protocols
medicine
Animals
Humans
Epidermal growth factor receptor
neoplasms
Mice, Inbred BALB C
Sulfonamides
biology
business.industry
MEK inhibitor
Diphenylamine
Cancer
Drug Synergism
MAP Kinase Kinase Kinases
medicine.disease
Xenograft Model Antitumor Assays
digestive system diseases
ErbB Receptors
chemistry
Mutation
biology.protein
Camptothecin
Female
KRAS
Colorectal Neoplasms
business
medicine.drug
Subjects
Details
- ISSN :
- 15573265 and 10780432
- Volume :
- 21
- Database :
- OpenAIRE
- Journal :
- Clinical Cancer Research
- Accession number :
- edsair.doi.dedup.....e1cbc148bbdb4e92819673a266370773