Dual Phosphoinositide 3-Kinase/Mammalian Target of Rapamycin Blockade Is an Effective Radiosensitizing Strategy for the Treatment of Non–Small Cell Lung Cancer Harboring K-RAS Mutations
Open accessPublished version of a preprint
Abstract
Non-small cell lung cancer (NSCLC) is a leading cause of cancer-related death worldwide. NSCLC often harbors oncogenic K-RAS mutations that lead to the aberrant activation of several intracellular networks including the phosphoinositide 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) signaling pathway. Oncogenic K-RAS predicts poor prognosis and resistance to treatment with ionizing radiation (IR). Oncogenic K-Ras expression in the respiratory epithelium is sufficient to initiate NSCLC tumorigenesis, which requires the catalytic subunit of PI3K. Thus, effective inhibition of the PI3K signaling should lead to significant antitumor effects. However, therapy with rapamycin analogues has yielded disappointing results due in part to compensatory up-regulation of AKT. We hypothesized that dual PI3K/mTOR blockade would overcome these limitations. We tested this hypothesis with BEZ235, a novel dual PI3K/mTOR inhibitor that has recently entered clinical development. We found that BEZ235 induces a striking antiproliferative effect both in transgenic mice with oncogenic K-RAS-induced NSCLC and in NSCLC cell lines expressing oncogenic K-RAS. We determined that treatment with BEZ235 was not sufficient to induce apoptosis. However, we found that dual PI3K/mTOR blockade effectively sensitizes NSCLC expressing oncogenic K-RAS to the proapoptotic effects of IR both in vitro and in vivo. We conclude that dual PI3K/mTOR blockade in combination with IR may benefit patients with NSCLC expressing oncogenic K-RAS. These findings may have general applicability in cancer therapy, because aberrant activation of PI3K occurs frequently in human cancer.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
mTOR inhibitors can sensitize other tumor types to radiation.
“Given that mTOR inhibitors can sensitize other tumor types to radiation (Eshleman et al., 2002; Konstantinidou et al., 2009; Murphy et al., 2009)”
From mTOR inhibition prevents epithelial stem cell senescence and protects from radiation-induced mucositis (2012) · cites this paper as Konstantinidou et al., 2009
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Lynch, T. J., Bell, D. W., Sordella, R., Gurubhagavatula, S., Okimoto, R. A., Brannigan, B. W., Harris, P. L., Haserlat, S. M., Supko, J. G., Haluska, F. G., et al. (2004) · New England Journal of Medicine · doi:10.1056/nejmoa040938 · Cited by 11,486 · see citing works
Jemal, A., Siegel, R. L., Ward, E., Hao, Y., Xu, J., Murray, T., & Thun, M. J. (2008) · CA A Cancer Journal for Clinicians · doi:10.3322/ca.2007.0010 · Cited by 10,184 · see citing works
<i>EGFR</i> Mutations in Lung Cancer: Correlation with Clinical Response to Gefitinib Therapy
Paez, J. G., Jänne, P. A., Lee, J. C., Tracy, S., Greulich, H., Gabriel, S., Herman, P., Kaye, F. J., Lindeman, N., Boggon, T. J., et al. (2004) · Science · doi:10.1126/science.1099314 · Cited by 9,368 · see citing works
Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex
Sarbassov, D. D., Guertin, D. A., Ali, S. M., & Sabatini, D. M. (2005) · Science · doi:10.1126/science.1106148 · Cited by 6,216 · see citing works
AKT/PKB signaling: navigating downstream
Manning, B. D., & Cantley, L. C. (2007) · Cell · doi:10.1016/j.cell.2007.06.009 · Cited by 6,115 · see citing works
Nicoletti, I., Migliorati, G., Pagliacci, M. C., Grignani, F., & Riccardi, C. (1991) · Journal of Immunological Methods · doi:10.1016/0022-1759(91)90198-o · Cited by 4,580 · see citing works
Pao, W., Miller, V., Zakowski, M., Doherty, J., Politi, K., Sarkaria, I., Singh, B., Heelan, R., Rusch, V., Fulton, L., et al. (2004) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0405220101 · Cited by 4,338 · see citing works
Clonogenic assay of cells in vitro
Franken, N. A. P., Rodermond, H. M., Stap, J., HAVEMAN, J., & Chris van, B. R. E. E. (2006) · Nature Protocols · doi:10.1038/nprot.2006.339 · Cited by 4,202 · see citing works
<i>EGFR</i> Mutation and Resistance of Non–Small-Cell Lung Cancer to Gefitinib
Kobayashi, S., Boggon, T. J., Dayaram, T., Jänne, P. A., Kocher, O., Meyerson, M., Johnson, B. E., Eck, M. J., Tenen, D. G., & Halmos, B. (2005) · New England Journal of Medicine · doi:10.1056/nejmoa044238 · Cited by 3,964 · see citing works
Pao, W., Miller, V. A., Politi, K. A., Riely, G. J., Somwar, R., Zakowski, M. F., Kris, M. G., & Varmus, H. (2005) · PLoS Medicine · doi:10.1371/journal.pmed.0020073 · Cited by 3,527 · see citing works
The evolution of phosphatidylinositol 3-kinases as regulators of growth and metabolism
Engelman, J. A., Luo, J., & Cantley, L. C. (2006) · Nature Reviews Genetics · doi:10.1038/nrg1879 · Cited by 3,330 · see citing works
Targeting RAS signalling pathways in cancer therapy
Downward, J. (2003) · Nature reviews. Cancer · doi:10.1038/nrc969 · Cited by 3,262 · see citing works
Somatic mutations affect key pathways in lung adenocarcinoma
Ding, L., Getz, G., Wheeler, D. A., Mardis, E. R., McLellan, M. D., Cibulskis, K., Sougnez, C., Greulich, H., Muzny, D. M., Morgan, M. B., et al. (2008) · Nature · doi:10.1038/nature07423 · Cited by 2,681 · see citing works
Ras, PI(3)K and mTOR signalling controls tumour cell growth
Shaw, R. J., & Cantley, L. C. (2006) · Nature · doi:10.1038/nature04869 · Cited by 2,019 · see citing works
KRAS Mutations and Primary Resistance of Lung Adenocarcinomas to Gefitinib or Erlotinib
Pao, W. J., Wang, T. Y., Riely, G. J., Miller, V. A., Pan, Q., Ladanyi, M., Zakowski, M. F., Heelan, R. T., Kris, M. G., & VARMUS, H. E. (2005) · PLoS Medicine · doi:10.1371/journal.pmed.0020017 · Cited by 1,517 · see citing works
Carracedo, A., Ma, L., Teruya-Feldstein, J., Rojo, F., Salmena, L., Alimonti, A., Egia, A., Sasaki, A. T., Thomas, G., Kozma, S. C., et al. (2008) · Journal of Clinical Investigation · doi:10.1172/jci34739 · Cited by 1,381 · see citing works
Engelman, J. A., Chen, L., Tan, X., Crosby, K., Guimaraes, A. R., Upadhyay, R., Maira, M., McNamara, K., Perera, S. A., Song, Y., et al. (2008) · Nature Medicine · doi:10.1038/nm.1890 · Cited by 1,330 · see citing works
Self-citationmTOR and cancer: insights into a complex relationship
Sabatini, D. M. (2006) · Nature Reviews Cancer · doi:10.1038/nrc1974 · Cited by 1,322 · see citing works
Cell death by mitotic catastrophe: a molecular definition
Castedo, M., Perfettini, J.-L., Roumier, T., Andreau, K., Medema, R., & Kroemer, G. (2004) · Oncogene · doi:10.1038/sj.onc.1207528 · Cited by 1,269 · see citing works
Sibling rivalry in the E2F family
Trimarchi, J. M., & Lees, J. A. (2002) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm714 · Cited by 1,158 · see citing works
Maira, S.-M., Stauffer, F., Brueggen, J., Furet, P., Schnell, C., Fritsch, C., Brachmann, S., Chène, P., De Pover, A., Schoemaker, K., et al. (2008) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-08-0017 · Cited by 1,134 · see citing works
Brognard, J., Clark, A. S., Ni, Y., & Dennis, P. A. (2001) · PubMed · Cited by 885 · see citing works
Phosphatidylinositol 3-kinase mutations identified in human cancer are oncogenic
Kang, S., Bader, A. G., & Vogt, P. K. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0408864102 · Cited by 827 · see citing works
Serra, V., Markman, B., Scaltriti, M., Eichhorn, P. J. A., Valero, V., Guzman, M., Botero, M. L., Llonch, E., Atzori, F., Di Cosimo, S., et al. (2008) · Cancer Research · doi:10.1158/0008-5472.can-08-1385 · Cited by 787 · see citing works
Self-citationThe genetics of the p53 pathway, apoptosis and cancer therapy
Vázquez, A., Bond, E. E., Levine, A. J., & Bond, G. L. (2008) · Nature Reviews Drug Discovery · doi:10.1038/nrd2656 · Cited by 674 · see citing works
Binding of Ras to Phosphoinositide 3-Kinase p110α Is Required for Ras- Driven Tumorigenesis in Mice
Gupta, S., Ramjaun, A. R., Haiko, P., Wang, Y., Warne, P. H., Nicke, B., Nye, E. L., Stamp, G., Alitalo, K. K., & Downward, J. (2007) · Cell · doi:10.1016/j.cell.2007.03.051 · Cited by 589 · see citing works
Fisher, G. H., Wellen, S. L., Klimstra, D., Lenczowski, J. M., Tichelaar, J. W., Lizak, M. J., Whitsett, J. A., Koretsky, A., & Varmus, H. E. (2001) · Genes & Development · doi:10.1101/gad.947701 · Cited by 582 · see citing works
Eichhorn, P. J. A., Gili, M., Scaltriti, M., Serra, V., Guzman, M., Nijkamp, W., Beijersbergen, R. L., Valero, V., Seoane, J., Bernards, R., et al. (2008) · Cancer Research · doi:10.1158/0008-5472.can-08-1740 · Cited by 499 · see citing works
PIK3CA Mutations and Copy Number Gains in Human Lung Cancers
Yamamoto, H., Shigematsu, H., Nomura, M., Lockwood, W. W., Sato, M., Okumura, N., Soh, J., Suzuki, M., Wistuba, I. I., Fong, K. M., et al. (2008) · Cancer Research · doi:10.1158/0008-5472.can-07-5084 · Cited by 429 · see citing works
Self-citationCancer-specific mutations in PIK3CA are oncogenic in vivo
Bader, A. G., Kang, S., & Vogt, P. K. (2006) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0510857103 · Cited by 421 · see citing works
PKBα/Akt1 Acts Downstream of DNA-PK in the DNA Double-Strand Break Response and Promotes Survival
Bozulic, L., Sürücü, B., Hynx, D., & Hemmings, B. A. (2008) · Molecular Cell · doi:10.1016/j.molcel.2008.02.024 · Cited by 386 · see citing works
NCI-navy medical oncology branch cell line data base
Phelps, R. M., Johnson, B. E., Ihde, D. C., Gazdar, A. F., Carbone, D. P., McClintock, P. R., Linnoila, R. I., Matthews, M. J., Bunn, P. A., Carney, D. N., et al. (1996) · Journal of Cellular Biochemistry · doi:10.1002/jcb.240630505 · Cited by 304 · see citing works
Self-citationA CK2-Dependent Mechanism for Degradation of the PML Tumor Suppressor
Scaglioni, P. P., Yung, T. M., Cai, L. F., Erdjument‐Bromage, H., Kaufman, A., Singh, B., Teruya‐Feldstein, J., Tempst, P., & Pandolfi, P. P. (2006) · Cell · doi:10.1016/j.cell.2006.05.041 · Cited by 293 · see citing works
Self-citationPalliative thoracic radiotherapy for lung cancer: a systematic review.
Fairchild, A., Harris, K., Barnes, E., Wong, R., Lutz, S., Bezjak, A., Cheung, P., & Chow, E. (2008) · Journal of Clinical Oncology · doi:10.1200/jco.2007.15.3312 · Cited by 266 · see citing works
The Ras radiation resistance pathway.
Gupta, A. K., Bakanauskas, V. J., Cerniglia, G. J., Cheng, Y., Bernhard, E. J., Muschel, R. J., & McKenna, W. G. (2001) · PubMed · Cited by 238 · see citing works
Kim, I., Bae, S.-S., Fernandes, A., Wu, J., Muschel, R. J., McKenna, W. G., Birnbaum, M. J., & Bernhard, E. J. (2005) · Cancer Research · doi:10.1158/0008-5472.can-05-0513 · Cited by 179 · see citing works
Schnell, C., Stauffer, F., ALLEGRINI, P. R., O’Reilly, T., McSheehy, P. M. J., Dartois, C., Stumm, M., Cozens, R. M., Littlewood-Evans, A. J., Garcia-Echeverria, C., et al. (2008) · Cancer Research · doi:10.1158/0008-5472.can-08-1044 · Cited by 175 · see citing works
Huncharek, M. S. (1999) · Carcinogenesis · doi:10.1093/carcin/20.8.1507 · Cited by 173 · see citing works
Targeting the Akt/mammalian target of rapamycin pathway for radiosensitization of breast cancer
Albert, J. M., Kim, K. W., Cao, C., & Lu, J. (2006) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-05-0400 · Cited by 173 · see citing works
Iwasa, T., Okamoto, I., Suzuki, M., Nakahara, T., Yamanaka, K., Hatashita, E., Yamada, Y., Fukuoka, M., Ono, K., & Nakagawa, K. (2008) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-08-0468 · Cited by 151 · see citing works
Wislez, M., Spencer, L., Izzo, J. G., Juroske, D. M., Balhara, K. S., CODY, D. D., Price, R. E., Hittelman, W. N., Wistuba, I. I., & Kurie, J. M. (2005) · Cancer Research · doi:10.1158/0008-5472.can-04-4420 · Cited by 150 · see citing works
PARP-1 modifies the effectiveness of p53-mediated DNA damage response
Valenzuela, M. T., Guerrero, R., Núñez, M. I., de Almodóvar, J. M. R., Sarker, M., de MURCIA, G., & Oliver, F. J. (2002) · Oncogene · doi:10.1038/sj.onc.1205169 · Cited by 124 · see citing works
Boothman, D. A., Greer, S. B., & Pardee, A. B. (1987) · PubMed · Cited by 74 · see citing works
Self-citationGene Mutations in Lung Cancer: Promising Predictive Factors for the Success of Molecular Therapy
Inoue, A., & Nukiwa, T. (2005) · PLoS Medicine · doi:10.1371/journal.pmed.0020013 · Cited by 28 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Toledo, L. I., Murga, M., Zur, R., Soria, R., Rodriguez, A., Martinez, S., Oyarzabal, J., Pastor, J., Bischoff, J. R., & Fernandez-Capetillo, O. (2011) · Nature Structural & Molecular Biology · doi:10.1038/nsmb.2076 · Cited by 465 · see citing works
Iglesias-Bartolome, R., Patel, V., Cotrim, A., Leelahavanichkul, K., Molinolo, A. A., Mitchell, J. B., & Gutkind, J. S. (2012) · Cell Stem Cell · doi:10.1016/j.stem.2012.06.007 · Cited by 284 · see citing works
RHOA-FAK is a required signaling axis for the maintenance of KRAS-driven lung adenocarcinomas
Konstantinidou, G., Ramadori, G., Torti, F., Kangasniemi, K., Ramirez, R. E., Cai, Y., Behrens, C., Dellinger, M. T., Brekken, R. A., Wistuba, I. I., et al. (2013) · Cancer Discovery · doi:10.1158/2159-8290.cd-12-0388 · Cited by 114 · see citing works
Self-citationTang, K.-J., Constanzo, J. D., Venkateswaran, N., Melegari, M., Ilcheva, M., Morales, J. C., Skoulidis, F., Heymach, J. V., Boothman, D. A., & Scaglioni, P. P. (2016) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-15-2603 · Cited by 91 · see citing works
Self-citation
- Authors
- Konstantinidou, G., Bey, E. A., Rabellino, A., Schuster, K., Maira, M. S., Gazdar, A. F., Amici, A., Boothman, D. A., & Scaglioni, P. P.
- Affiliations
- Università di Camerino (IT)
- Harold C. Simmons Comprehensive Cancer Center (US)
- 1Division of Hematology and Oncology,
- Novartis (Switzerland) (CH)
- The University of Texas Southwestern Medical Center (US)
- Corresponding author
- Scaglioni, Pier Paolo
- ORCID
- Venue
- Cancer Research
- Published
- 2009-10-01
- Volume
- 69
- Issue
- 19
- Pages
- 7644-7652
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- PMC
- PMC2760010
- OpenAlex
- W2119886330
- Cited by
- 142
- References
- 44
- Citations by year
- 2025: 3 · 2024: 1 · 2023: 3 · 2022: 5 · 2021: 2 · 2020: 7 · 2019: 3 · 2018: 2 · 2017: 9 · 2016: 13 · 2015: 10 · 2014: 17 · 2013: 20 · 2012: 22
- FWCI
- 6.31
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- U.S. Department of Energy (DE‐FG02‐)
- Concern Foundation
- American-Italian Cancer Foundation
- Università degli Studi di Camerino
- National Institutes of Health
- National Cancer Institute (P50CA070907, K08CA112325, R01CA102792, P30CA142543)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Keywords
- non-small cell lung cancer, KRAS mutation, BEZ235, radiosensitization, ionizing radiation, Akt activation, apoptosis, antiproliferative activity
- MeSH terms
- Phosphoinositide-3 Kinase Inhibitors, Animals, Carcinoma, Non-Small-Cell Lung, Combined Modality Therapy, Female, Humans, Imidazoles, Lung Neoplasms, Mice, Nude, Mutation, Protein Kinases, Quinolines, Radiation-Sensitizing Agents, Genes, ras, Apoptosis, Phosphatidylinositol 3-Kinases, Xenograft Model Antitumor Assays, Cell Line, Tumor, Mice, TOR Serine-Threonine Kinases
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
