The DOI matches its Crossref record; 31 of the 31 references it cites were found in a registry or an index.
Inhibition of MEK and PI3K/mTOR Suppresses Tumor Growth but Does Not Cause Tumor Regression in Patient-Derived Xenografts of RAS-Mutant Colorectal Carcinomas
Open accessPublished version of a preprint
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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Cites
Cetuximab and Chemotherapy as Initial Treatment for Metastatic Colorectal Cancer
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mTOR Inhibition Induces Upstream Receptor Tyrosine Kinase Signaling and Activates Akt
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RAF inhibitors transactivate RAF dimers and ERK signalling in cells with wild-type BRAF
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Wild-Type BRAF Is Required for Response to Panitumumab or Cetuximab in Metastatic Colorectal Cancer
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“Analyte extraction and mutational profiling were done as described (14, 19, 22, 23).”
Self-citationKinase-Dead BRAF and Oncogenic RAS Cooperate to Drive Tumor Progression through CRAF
Heidorn, S. J., Milagre, C. S., Whittaker, S. R., Nourry, A., Niculescu‐Duvaz, I., Dhomen, N. S., Hussain, J., Reis-Filho, J. S., Springer, C. J., Pritchard, C. A., et al. (2010) · Cell · doi:10.1016/j.cell.2009.12.040 · Cited by 1,497
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Patient-Derived Xenograft Models: An Emerging Platform for Translational Cancer Research
Hidalgo, M. M., Amant, F. C., Biankin, A. V., Budínská, E., Byrne, A. T., Caldas, C., Clarke, R. B., de Jong, S., Jonkers, J., Mælandsmo, G. M., et al. (2014) · Cancer Discovery · doi:10.1158/2159-8290.cd-14-0001 · Cited by 1,797
Self-citationGao, H., Korn, J. M., Ferretti, S., Monahan, J. E., Wang, Y., Singh, M., Zhang, C., Schnell, C., Yang, G., Zhang, Y., et al. (2015) · Nature Medicine · doi:10.1038/nm.3954 · Cited by 1,393
Interrogating open issues in cancer precision medicine with patient-derived xenografts
Byrne, A. T., Alférez, D., Amant, F. C., Annibali, D., Arribas, J., Biankin, A. V., Bruna, A., Budínská, E., Caldas, C., Chang, D. K.-F., et al. (2017) · Nature reviews. Cancer · doi:10.1038/nrc.2016.140 · Cited by 683
Self-citationAmplification of the MET Receptor Drives Resistance to Anti-EGFR Therapies in Colorectal Cancer
Bardelli, A., Corso, S., Bertotti, A., Hobor, S., Valtorta, E., Siravegna, G., Sartore-Bianchi, A., Scala, E., Cassingena, A., Zecchin, D., et al. (2013) · Cancer Discovery · doi:10.1158/2159-8290.cd-12-0558 · Cited by 657
Self-citationThe Hippo effector YAP promotes resistance to RAF- and MEK-targeted cancer therapies
Lin, L., Sabnis, A. J., Chan, E., Olivas, V., Cade, L., Pazarentzos, E., Asthana, S., Neel, D., Yan, J. J., Lu, X., et al. (2015) · Nature Genetics · doi:10.1038/ng.3218 · Cited by 551
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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