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Inhibition of MEK and PI3K/mTOR Suppresses Tumor Growth but Does Not Cause Tumor Regression in Patient-Derived Xenografts of RAS-Mutant Colorectal Carcinomas
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Abstract
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.
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“Although BEZ235 showed satisfactory antitumor activity against various cancer types in a preclinical model, poor tolerability and high adverse events were observed in clinical trials38–41.”
From Mechanisms of KRAS inhibitor resistance in KRAS-mutant colorectal cancer harboring Her2 amplification and aberrant KRAS localization (2025) · cites this paper as [41]
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“Although BEZ235 showed satisfactory antitumor activity against various cancer types in a preclinical model, poor tolerability and high adverse events were observed in clinical trials38–41.”
From Mechanisms of KRAS inhibitor resistance in KRAS-mutant colorectal cancer harboring Her2 amplification and aberrant KRAS localization (2025) · cites this paper as [41]
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Metadata
- Authors
- Migliardi, G., Sassi, F., Torti, D., Galimi, F., Zanella, E. R., Buscarino, M., Ribero, D., Muratore, A., Massucco, P., Pisacane, A., Risio, M., Capussotti, L., Marsoni, S., Di Nicolantonio, F., Bardelli, A., Comoglio, P. M., Trusolino, L., & Bertotti, A.
- Affiliations
- Candiolo Cancer Institute (IT)
- Authors' Affiliations: 1Laboratory of Molecular Pharmacology, 2Laboratory of Molecular Genetics, 3Division of Surgical Oncology, 4Unit of Pathology, 5Clinical Coordination Unit, 6Molecular Clinical Oncology, Institute for Cancer Research and Treatment (IRCC); 7Department of Oncological Sciences, University of Torino Medical School, Candiolo; 8Department of Surgery, Mauriziano Umberto I Hospital, Torino; 9Southern Europe New Drug Organization (SENDO) Foundation; and 10FIRC Institute of Molecular Oncology (IFOM), Milano, Italy
- ORCID
- Venue
- Clinical Cancer Research
- Published
- 2012-04-30
- Volume
- 18
- Issue
- 9
- Pages
- 2515-2525
- ISSN
- 1078-0432 (ISSN-L)
- 1557-3265
- OpenAlex
- W2096218887
- Semantic Scholar
- e3d0b63472624f0def1ca1f4023cc3c8049077f4
- Cited by
- 191
- References
- 31
- Citations by year
- 2026: 1 · 2025: 4 · 2024: 5 · 2023: 7 · 2022: 8 · 2021: 12 · 2020: 15 · 2019: 20 · 2018: 23 · 2017: 15 · 2016: 15 · 2015: 22 · 2014: 21 · 2013: 17 · 2012: 6
- FWCI
- 10.37
- Type
- journal article
- Language
- en
- Open access
- green
- hdl.handle.net
- Licence
- other-oa
- Locations
- Clinical Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- Institutional Research Information System University of Turin (University of Turin) (submittedVersion, other-oa)
- Funders
- Regione Piemonte
- Topics
- Health Sciences › Medicine › Oncology › Colorectal Cancer Treatments and Studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Melanoma and MAPK Pathways
- Keywords
- metastatic colorectal cancer, MEK inhibition, PI3K/mTOR inhibition, selumetinib, BEZ235, cetuximab, combination therapy, patient-derived xenografts, KRAS mutation, NRAS mutation, BRAF mutation, PIK3CA mutation, PI3K/Akt signaling, tumor growth inhibition, tumor regression, anti-EGFR therapy resistance, NOD/SCID mice
- MeSH terms
- Aged, Aged, 80 and over, Animals, Colon, Female, Humans, Immunoenzyme Techniques, Liver Neoplasms, Male, Middle Aged, Mutation, Genes, ras, Rectum, Colorectal Neoplasms, Case-Control Studies, Mice, SCID, Mice, Inbred NOD, 1-Phosphatidylinositol 4-Kinase, Mitogen-Activated Protein Kinase Kinases, Xenograft Model Antitumor Assays, Cell Line, Tumor, Protein Kinase Inhibitors, Extracellular Signal-Regulated MAP Kinases, Proto-Oncogene Proteins B-raf, Mice, TOR Serine-Threonine Kinases
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