Afatinib restrains K-RAS–driven lung tumorigenesis

Moll, Herwig P.; Pranz, Klemens; Musteanu, Monica; Grabner, Beatrice; Hruschka, Natascha; Mohrherr, Julian; Aigner, Petra; Stiedl, Patricia; Brcic, Luka; Laszlo, Viktoria; Schramek, Daniel; Moriggl, Richard; Eferl, Robert; Moldvay, Judit; Dezso, Katalin; Lopez-Casas, Pedro P.; Stoiber, Dagmar; Hidalgo, Manuel; Penninger, Josef; Sibilia, Maria; Győrffy, Balázs; Barbacid, Mariano; Dome, Balázs; Popper, Helmut; Casanova, Emilio

doi:10.1126/scitranslmed.aao2301

Cited by 127Lung Cancer Treatments and MutationsProtein Kinase Regulation and GTPase SignalingHER2/EGFR in Cancer Research

Afatinib restrains K-RAS–driven lung tumorigenesis

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Moll, Herwig P., Pranz, Klemens, Musteanu, Monica, Grabner, Beatrice, Hruschka, Natascha, Mohrherr, Julian, Aigner, Petra, Stiedl, Patricia +17 more·2018·Science Translational Medicine

DOI 10.1126/scitranslmed.aao2301PMC PMC7610658

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Abstract

K-RAS –mutated lung adenocarcinomas depend on ERBB signaling, and pan-ERBB inhibitors impair K-RAS–driven lung tumorigenesis.

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Crossref · 10.1126/scitranslmed.aao2301

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In NSCLCs and CRCs, KRASG12C inhibition leads to accumulation of activated upstream EGFR and/or other ERBB family members, facilitating escape from KRASG12C-inhibitor monotherapy.
“In NSCLCs and CRCs, KRASG12C inhibition leads to an accumulation of activated upstream EGFR and/or other ERBB family members, which facilitates escape from KRASG12C-inhibitor monotherapy110,121–124.”
From The current state of the art and future trends in RAS-targeted cancer therapies (2022) · cites this paper as [124]
Afatinib blocked compensatory ERBB2 and ERBB3 activation, whereas erlotinib and gefitinib did not.
“afatinib blocked compensatory ERBB2 and ERBB3 activation, whereas erlotinib and gefitinib did not.”
From New Horizons in KRAS-Mutant Lung Cancer: Dawn After Darkness (2019) · cites this paper as [62]
Genetic mouse models revealed that EGFR deletion attenuates mutant KRAS activity and transiently reduces tumor growth.
“Genetic mouse models revealed that EGFR deletion attenuates mutant KRAS activity and transiently reduces tumor growth.”
From New Horizons in KRAS-Mutant Lung Cancer: Dawn After Darkness (2019) · cites this paper as [62]
Both studies revealed a requirement for simultaneous inhibition of multiple ERBB while targeting a single member of the family was not effective.
“Notably, both studies revealed a requirement for simultaneous inhibition of multiple ERBB while targeting a single member of the family was not effective.”
From New Horizons in KRAS-Mutant Lung Cancer: Dawn After Darkness (2019) · cites this paper as [62]
EGFR inhibition initiated a rapid resistance mechanism involving non-EGFR ERBB family members, which triggered a tumor escape mechanism.
“EGFR inhibition initiated a rapid resistance mechanism involving non-EGFR ERBB family members, which triggered a tumor escape mechanism.”
From New Horizons in KRAS-Mutant Lung Cancer: Dawn After Darkness (2019) · cites this paper as [62]

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“Thus, a pan-ERBB inhibitor, afatinib, effectively inhibited tumor growth of KRAS-mutated NSCLC on patient- or cell line– derived xenografts (44).”
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Post, J. B., Hami, N., Lohuis, J. O., van de Ven, M., de Korte‐Grimmerink, R., Stangl, C., Stelloo, E., Verlaan-Klink, I., van Rheenen, J., & Snippert, H. J. G. (2019) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/860122 · Cited by 3 · see citing works
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Abstract 809: Afatinib restrains K-RAS driven lung tumorigenesis
Moll, H. P., Pranz, K., Musteanu, M., Brčić, L., Popper, H., Moldvay, J., Döme, B., & Casanova, E. (2018) · Cancer Research · doi:10.1158/1538-7445.am2018-809 · Cited by 2 · see citing works
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Breaking bad family ties: Pan-ERBB blockers inhibit KRAS driven lung tumorigenesis
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PO-211 KRAS driven lung adenocarcinoma depends on ERBB signalling
Moll, H. P., Pranz, K., Musteanu, M., Grabner, B., Hruschka, N., Mohrherr, J., Barbacid, M., Döme, B., Popper, H., & Casanova, E. (2018) · ESMO Open · doi:10.1136/esmoopen-2018-eacr25.729
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KRAS mutated lung adenocarcinoma responds to pan-ERBB and Aurora kinase inhibitors
Uras, I. Z., Trkulja, M. V., Salama, A. K. A. A., Horvath, J., Asnani, K., Trenk, C., Kubicek, S., Bilban, M., Moll, H. P., & Casanova, E. (2026) · npj Precision Oncology · doi:10.1038/s41698-025-01242-8 · Cited by 1 · see citing works
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The ERBB network facilitates KRAS-driven lung tumorigenesis
Kruspig, B., Monteverde, T., Neidler, S., Hock, A., Kerr, E., Nixon, C., Clark, W., Hedley, A., Laing, S., Coffelt, S. B., et al. (2018) · Science Translational Medicine · doi:10.1126/scitranslmed.aao2565 · Cited by 111 · see citing works

Authors: Moll, H. P., Pranz, K., Musteanu, M., Grabner, B., Hruschka, N., Mohrherr, J., Aigner, P., Stiedl, P., Brcic, L., Laszlo, V., Schramek, D., Moriggl, R., Eferl, R., Moldvay, J., Dezso, K., Lopez-Casas, P. P., Stoiber, D., Hidalgo, M., Penninger, J., Sibilia, M., Győrffy, B., Barbacid, M., Dome, B., Popper, H., & Casanova, E.
Affiliations: Comprehensive Cancer Center Vienna (AT)
Ludwig Boltzmann Institute for Cancer Research (AT)
Spanish National Cancer Research Centre, E-28029 Madrid, Spain.
Institute of Pathology, Medical University of Graz, AT-8036 Graz, Austria.
Division of Thoracic Surgery, Department of Surgery and CCC, Medical University of Vienna, AT-1090 Vienna, Austria.
Institute of Molecular Biotechnology (AT)
University of Veterinary Medicine Vienna (AT)
Semmelweis University (HU)
First Department of Pathology and Experimental Cancer Research, Semmelweis University, HU-1122 Budapest, Hungary.
Spanish National Cancer Research Centre (ES)
Medical University of Graz (AT)
Corresponding author: Casanova, Emilio
ORCID: Moll, Herwig P.
Pranz, Klemens
Musteanu, Monica
Brcic, Luka
Laszlo, Viktoria
Schramek, Daniel
Moriggl, Richard
Eferl, Robert
Moldvay, Judit
Lopez-Casas, Pedro P.
Stoiber, Dagmar
Hidalgo, Manuel
Penninger, Josef
Sibilia, Maria
Győrffy, Balázs
Barbacid, Mariano
Dome, Balázs
Popper, Helmut
Casanova, Emilio
Venue: Science Translational Medicine
Publisher: American Association for the Advancement of Science (AAAS)
Published: 2018-06-20
Volume: 10
Issue: 446
ISSN: 1946-6234 (ISSN-L)
1946-6242
DOI: 10.1126/scitranslmed.aao2301
PMC: PMC7610658
OpenAlex: W2808999647
Cited by: 125
References: 51
Citations by year: 2026: 4 · 2025: 8 · 2024: 8 · 2023: 11 · 2022: 18 · 2021: 21 · 2020: 22 · 2019: 23 · 2018: 9 · 2016: 1
FWCI: 14.32
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Locations: Science Translational Medicine (publishedVersion)
PubMed (publishedVersion)
Repository of the Academy's Library (Library of the Hungarian Academy of Sciences) (acceptedVersion)
PubMed Central (acceptedVersion)
Semmelweis University Repository (Semmelweis University) (submittedVersion)
Funders: Austrian Science Fund (FWF-P25599-B19, SFB-F4707, SFB-F06105)
Fellinger Krebsforschungsverein
National Research, Development and Innovation Office, Hungary (NVKP_16-1-2016-0037)
Hungarian NRDI Office (K109626, K108465, KNN121510, SNN114490)
Hungarian Academy of Science
Topics: 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
Health Sciences › Medicine › Oncology › HER2/EGFR in Cancer Research
Keywords: afatinib, KRAS mutation, lung adenocarcinoma, lung carcinogenesis, ErbB signaling, pan-ErbB inhibitor, EGFR, HER2, HER3, ErbB4, tyrosine kinase inhibitors
MeSH terms: Erlotinib Hydrochloride, Gefitinib, Adenocarcinoma of Lung, Afatinib, Humans, Lung Neoplasms, Mutation, Signal Transduction, Proto-Oncogene Proteins p21(ras), Drug Resistance, Neoplasm, Cell Line, Tumor, Cell Proliferation, Carcinogenesis, ErbB Receptors

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