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Cited by 319PI3K/AKT/mTOR signaling in cancerLung Cancer Treatments and MutationsHER2/EGFR in Cancer Research

The DOI matches its Crossref record; 7 of the 7 references it cites were found in a registry or an index.

Differential induction of apoptosis in HER2 and EGFR addicted cancers following PI3K inhibition

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Faber, Anthony C., Li, Danan, Song, YoungChul, Liang, Mei-Chih, Yeap, Beow Y., Bronson, Roderick T., Lifshits, Eugene, Chen, Zhao, Maira, Sauveur-Michel, García-Echeverría, Carlos, Wong, Kwok-Kin, Engelman, Jeffrey A.·2009·Proceedings of the National Academy of Sciences
DOI 10.1073/pnas.0905056106PMC PMC2765921
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Abstract

Non-small cell lung cancers with activating mutations in the epidermal growth factor receptor ( EGFR ) are highly responsive to EGFR tyrosine kinase inhibitors (TKIs), such as gefitinib and erlotinib. Such cancers are “addicted” to EGFR, and treatment with a TKI invariably leads to down-regulation of the PI3K-AKT-mTOR and MEK-ERK signaling pathways, resulting in apoptosis. Using a dual PI3K-mTOR inhibitor, NVP-BEZ235, we evaluated whether PI3K-mTOR inhibition alone induced apoptosis in these cancers. In contrast to HER2 -amplified breast cancers, we found that PI3K-mTOR inhibition did not promote substantial apoptosis in the EGFR mutant lung cancers. However, blocking both PI3K-mTOR and MEK simultaneously led to apoptosis to similar levels as the EGFR TKIs, suggesting that down-regulation of these pathways may account for much of the apoptosis promoted by EGFR inhibition. In EGFR mutant lung cancers, down-regulation of both intracellular pathways converged on the BH3 family of proteins regulating apoptosis. PI3K inhibition led to down-regulation of Mcl-1, and MEK inhibition led to up-regulation of BIM. In fact, down-regulation of Mcl-1 by siRNA was sufficient to sensitize these cancers to single-agent MEK inhibitors. Surprisingly, an AKT inhibitor did not decrease Mcl-1 levels, and when combined with MEK inhibitors, failed to induce apoptosis. Importantly, we observed that the combination of PI3K-mTOR and MEK inhibitors effectively shrunk tumors in a transgenic and xenograft model of EGFR T790M-L858R cancers. These data indicate simultaneous inhibition of PI3K-mTOR and MEK signaling is an effective strategy for treating EGFR mutant lung cancers, including those with acquired resistance to EGFR TKIs.

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  • TORC1 inhibition, via loss of 4EBP1 phosphorylation, results in a decrease of MCL-1 protein expression in some cancers.

    “TORC1 inhibition, via loss of 4EBP1 (also referred to as EIF4EBP1) phosphorylation, results in a decrease of MCL-1 protein expression in these cancers (37–40).”

    From mTOR Inhibition Specifically Sensitizes Colorectal Cancers with KRAS or BRAF Mutations to BCL-2/BCL-XL Inhibition by Suppressing MCL-1 (2014) · cites this paper as [39]

    The Discussion reports that rapamycin, an mTOR inhibitor, reduces Mcl-1 levels in several lymphoma and leukemia models. It does not attribute that reduction to loss of 4EBP1 phosphorylation; moreover, it says loss of mTORC1 activity did not reproduce Mcl-1 loss in the EGFR-mutant lung cancer cells studied here. (LLM, conf=0.88)

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Metadata

Authors
Faber, A. C., Li, D., Song, Y., Liang, M.-C., Yeap, B. Y., Bronson, R. T., Lifshits, E., Chen, Z., Maira, S.-M., García-Echeverría, C., Wong, K.-K., & Engelman, J. A.
Affiliations
  • Harvard University (US)
  • Dana-Farber Cancer Institute (US)
  • Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115;
  • Novartis (Switzerland) (CH)
  • Novartis Institutes for BioMedical Research, Novartis Oncology, CH-4002 Basel, Switzerland
ORCID
Venue
Proceedings of the National Academy of Sciences
Publisher
National Academy of Sciences
Published
2009-11-17
Volume
106
Issue
46
Pages
19503-19508
ISSN
  • 0027-8424 (ISSN-L)
  • 1091-6490
DOI
10.1073/pnas.0905056106
PMC
PMC2765921
OpenAlex
W2004691500
Cited by
319
References
7
Citations by year
2026: 6 · 2025: 8 · 2024: 5 · 2023: 20 · 2022: 9 · 2021: 9 · 2020: 4 · 2019: 6 · 2018: 13 · 2017: 15 · 2016: 14 · 2015: 25 · 2014: 40 · 2013: 45 · 2012: 35
FWCI
10.88
Type
journal article
Language
en
Open access
Locations
  • Proceedings of the National Academy of Sciences (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • The Mouseion at the JAXlibrary (Jackson Laboratory) (submittedVersion)
Funders
  • V Foundation for Cancer Research
  • Massachusetts General Hospital
  • Flight Attendant Medical Research Institute
  • Dartmouth College
  • National Institutes of Health
  • National Institute on Aging (R01AG2400401, K08AG024004)
  • National Cancer Institute (P50CA127003, R01CA122794, R01CA140594, P50CA090578, K08CA120060, R01CA137008)
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
  • Health Sciences › Medicine › Oncology › HER2/EGFR in Cancer Research
Keywords
PI3K/mTOR inhibition, MEK inhibition, EGFR-mutant non-small cell lung cancer, HER2-amplified breast cancer, apoptosis, gefitinib resistance, erlotinib resistance, Mcl-1, building information modeling, AKT inhibition, combination therapy, NVP-BEZ235
MeSH terms
Erlotinib Hydrochloride, Gefitinib, Phosphoinositide-3 Kinase Inhibitors, Animals, Antineoplastic Combined Chemotherapy Protocols, Breast Neoplasms, Carcinoma, Non-Small-Cell Lung, Female, Humans, Imidazoles, Lung Neoplasms, Protein Kinases, Quinazolines, Quinolines, Apoptosis, Erb-b2 Receptor Tyrosine Kinases, MAP Kinase Kinase Kinases, Xenograft Model Antitumor Assays, Cell Line, Tumor, Protein Kinase Inhibitors, Mice, TOR Serine-Threonine Kinases, ErbB Receptors

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