Inhibition of MEK and PI3K/mTOR Suppresses Tumor Growth but Does Not Cause Tumor Regression in Patient-Derived Xenografts of RAS-Mutant Colorectal Carcinomas
| Autor: | Federica Di Nicolantonio, Francesco Galimi, Paolo Massucco, Andrea Bertotti, Alberto Bardelli, Eugenia R. Zanella, Michela Buscarino, Giorgia Migliardi, Livio Trusolino, Lorenzo Capussotti, Davide Torti, Dario Ribero, Silvia Marsoni, Francesco Sassi, Mauro Risio, Alberto Pisacane, Paolo M. Comoglio, Andrea Muratore |
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| Rok vydání: | 2012 |
| Předmět: |
Male
MAPK/ERK pathway Neuroblastoma RAS viral oncogene homolog Cancer Research Mice SCID Gene mutation medicine.disease_cause Immunoenzyme Techniques Mice 0302 clinical medicine Mice Inbred NOD Extracellular Signal-Regulated MAP Kinases 1-Phosphatidylinositol 4-Kinase Aged 80 and over 0303 health sciences Cetuximab Kinase TOR Serine-Threonine Kinases Liver Neoplasms Middle Aged 3. Good health Oncology 030220 oncology & carcinogenesis Female KRAS Colorectal Neoplasms medicine.drug Proto-Oncogene Proteins B-raf medicine.medical_specialty Colon 03 medical and health sciences Cell Line Tumor Internal medicine medicine Animals Humans Protein Kinase Inhibitors PI3K/AKT/mTOR pathway Aged 030304 developmental biology Mitogen-Activated Protein Kinase Kinases business.industry Rectum Cancer medicine.disease Xenograft Model Antitumor Assays Genes ras Endocrinology Case-Control Studies Mutation Cancer research business |
| Zdroj: | Clinical Cancer Research Clinical Cancer Research; Vol 18 |
| ISSN: | 1557-3265 1078-0432 |
| Popis: | Purpose: Gene mutations along the Ras pathway (KRAS, NRAS, BRAF, PIK3CA) occur in approximately 50% of colorectal cancers (CRC) and correlate with poor response to anti–EGF receptor (EGFR) therapies. We assessed the effects of mitogen-activated protein (MAP)/extracellular signal-regulated kinase (ERK) kinase (MEK) and phosphoinositide 3-kinase (PI3K)/mTOR inhibitors, which neutralize the major Ras effectors, in patient-derived xenografts from RAS/RAF/PIK3CA-mutant metastatic CRCs (mCRC). Experimental Design: Forty mCRC specimens harboring KRAS, NRAS, BRAF, and/or PIK3CA mutations were implanted in nonobese diabetic/severe combined immunodeficient (NOD/SCID) mice. Each xenograft was expanded into four treatment arms: placebo, the MEK inhibitor AZD6244, the PI3K/mTOR inhibitor, BEZ235, or AZD6244 + BEZ235. Cases initially treated with placebo crossed over to AZD6244, BEZ235, and the anti-EGFR monoclonal antibody cetuximab. Results: At the 3-week evaluation time point, cotreatment of established tumors with AZD6244 + BEZ235 induced disease stabilization in the majority of cases (70%) but did not lead to overt tumor regression. Monotherapy was less effective, with BEZ235 displaying higher activity than AZD6244 (disease control rates, DCRs: AZD6244, 27.5%; BEZ235, 42.5%). Triple therapy with cetuximab provided further advantage (DCR, 88%). The extent of disease control declined at the 6-week evaluation time point (DCRs: AZD6244, 13.9%; BEZ235, 16.2%; AZD6244 + BEZ235, 34%). Cross-analysis of mice harboring xenografts from the same original tumor and treated with each of the different modalities revealed subgroups with preferential sensitivity to AZD6244 (12.5%), BEZ235 (35%), or AZD6244 + BEZ235 (42.5%); another subgroup (10%) showed equivalent response to any treatment. Conclusions: The prevalent growth-suppressive effects produced by MEK and PI3K/mTOR inhibition suggest that this strategy may retard disease progression in patients. However, data offer cautionary evidence against the occurrence of durable responses. Clin Cancer Res; 18(9); 2515–25. ©2012 AACR. |
| Databáze: | OpenAIRE |
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