Activation of CD44/PAK1/AKT signaling promotes resistance to FGFR1 inhibition in squamous-cell lung cancer
Abstract Lung cancer is the leading cause of cancer-related deaths worldwide. Fibroblast growth factor receptor 1 (FGFR1) gene amplification is one of the most prominent and potentially targetable genetic alterations in squamous-cell lung cancer (SQCLC). Highly selective tyrosine kinase inhibitors h...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2022-07-01
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| Series: | npj Precision Oncology |
| Online Access: | https://doi.org/10.1038/s41698-022-00296-2 |
| _version_ | 1797642315588698112 |
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| author | Omar Elakad Björn Häupl Vera Labitzky Sha Yao Stefan Küffer Alexander von Hammerstein-Equord Bernhard C. Danner Manfred Jücker Henning Urlaub Tobias Lange Philipp Ströbel Thomas Oellerich Hanibal Bohnenberger |
| author_facet | Omar Elakad Björn Häupl Vera Labitzky Sha Yao Stefan Küffer Alexander von Hammerstein-Equord Bernhard C. Danner Manfred Jücker Henning Urlaub Tobias Lange Philipp Ströbel Thomas Oellerich Hanibal Bohnenberger |
| author_sort | Omar Elakad |
| collection | DOAJ |
| description | Abstract Lung cancer is the leading cause of cancer-related deaths worldwide. Fibroblast growth factor receptor 1 (FGFR1) gene amplification is one of the most prominent and potentially targetable genetic alterations in squamous-cell lung cancer (SQCLC). Highly selective tyrosine kinase inhibitors have been developed to target FGFR1; however, resistance mechanisms originally existing in patients or acquired during treatment have so far led to limited treatment efficiency in clinical trials. In this study we performed a wide-scale phosphoproteomic mass-spectrometry analysis to explore signaling pathways that lead to resistance toward FGFR1 inhibition in lung cancer cells that display (i) intrinsic, (ii) pharmacologically induced and (iii) mutationally induced resistance. Additionally, we correlated AKT activation to CD44 expression in 175 lung cancer patient samples. We identified a CD44/PAK1/AKT signaling axis as a commonly occurring resistance mechanism to FGFR1 inhibition in lung cancer. Co-inhibition of AKT/FGFR1, CD44/FGFR1 or PAK1/FGFR1 sensitized ‘intrinsically resistant’ and ‘induced-resistant’ lung-cancer cells synergetically to FGFR1 inhibition. Furthermore, strong CD44 expression was significantly correlated with AKT activation in SQCLC patients. Collectively, our phosphoproteomic analysis of lung-cancer cells resistant to FGFR1 inhibitor provides a large data library of resistance-associated phosphorylation patterns and leads to the proposal of a common resistance pathway comprising CD44, PAK1 and AKT activation. Examination of CD44/PAK1/AKT activation could help to predict response to FGFR1 inhibition. Moreover, combination between AKT and FGFR1 inhibitors may pave the way for an effective therapy of patients with treatment-resistant FGFR1-dependent lung cancer. |
| first_indexed | 2024-03-11T13:58:17Z |
| format | Article |
| id | doaj.art-95f49f3dedb14887b6c8d296c622f61d |
| institution | Directory Open Access Journal |
| issn | 2397-768X |
| language | English |
| last_indexed | 2024-03-11T13:58:17Z |
| publishDate | 2022-07-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | npj Precision Oncology |
| spelling | doaj.art-95f49f3dedb14887b6c8d296c622f61d2023-11-02T05:45:33ZengNature Portfolionpj Precision Oncology2397-768X2022-07-016111410.1038/s41698-022-00296-2Activation of CD44/PAK1/AKT signaling promotes resistance to FGFR1 inhibition in squamous-cell lung cancerOmar Elakad0Björn Häupl1Vera Labitzky2Sha Yao3Stefan Küffer4Alexander von Hammerstein-Equord5Bernhard C. Danner6Manfred Jücker7Henning Urlaub8Tobias Lange9Philipp Ströbel10Thomas Oellerich11Hanibal Bohnenberger12Institute of Pathology, University Medical CenterDepartment of Medicine II, Hematology/Oncology, Goethe UniversityInstitute for Anatomy and Experimental Morphology, University Cancer Center, University Medical Center Hamburg-EppendorfInstitute of Pathology, University Medical CenterInstitute of Pathology, University Medical CenterDepartment of Thoracic and Cardiovascular Surgery, University Medical CenterDepartment of Thoracic and Cardiovascular Surgery, University Medical CenterCenter for Experimental Medicine, Institute of Biochemistry and Signal Transduction, University Medical Center Hamburg-EppendorfBioanalytical Mass Spectrometry Group, Max Planck Institute for Biophysical ChemistryInstitute for Anatomy and Experimental Morphology, University Cancer Center, University Medical Center Hamburg-EppendorfInstitute of Pathology, University Medical CenterDepartment of Medicine II, Hematology/Oncology, Goethe UniversityInstitute of Pathology, University Medical CenterAbstract Lung cancer is the leading cause of cancer-related deaths worldwide. Fibroblast growth factor receptor 1 (FGFR1) gene amplification is one of the most prominent and potentially targetable genetic alterations in squamous-cell lung cancer (SQCLC). Highly selective tyrosine kinase inhibitors have been developed to target FGFR1; however, resistance mechanisms originally existing in patients or acquired during treatment have so far led to limited treatment efficiency in clinical trials. In this study we performed a wide-scale phosphoproteomic mass-spectrometry analysis to explore signaling pathways that lead to resistance toward FGFR1 inhibition in lung cancer cells that display (i) intrinsic, (ii) pharmacologically induced and (iii) mutationally induced resistance. Additionally, we correlated AKT activation to CD44 expression in 175 lung cancer patient samples. We identified a CD44/PAK1/AKT signaling axis as a commonly occurring resistance mechanism to FGFR1 inhibition in lung cancer. Co-inhibition of AKT/FGFR1, CD44/FGFR1 or PAK1/FGFR1 sensitized ‘intrinsically resistant’ and ‘induced-resistant’ lung-cancer cells synergetically to FGFR1 inhibition. Furthermore, strong CD44 expression was significantly correlated with AKT activation in SQCLC patients. Collectively, our phosphoproteomic analysis of lung-cancer cells resistant to FGFR1 inhibitor provides a large data library of resistance-associated phosphorylation patterns and leads to the proposal of a common resistance pathway comprising CD44, PAK1 and AKT activation. Examination of CD44/PAK1/AKT activation could help to predict response to FGFR1 inhibition. Moreover, combination between AKT and FGFR1 inhibitors may pave the way for an effective therapy of patients with treatment-resistant FGFR1-dependent lung cancer.https://doi.org/10.1038/s41698-022-00296-2 |
| spellingShingle | Omar Elakad Björn Häupl Vera Labitzky Sha Yao Stefan Küffer Alexander von Hammerstein-Equord Bernhard C. Danner Manfred Jücker Henning Urlaub Tobias Lange Philipp Ströbel Thomas Oellerich Hanibal Bohnenberger Activation of CD44/PAK1/AKT signaling promotes resistance to FGFR1 inhibition in squamous-cell lung cancer npj Precision Oncology |
| title | Activation of CD44/PAK1/AKT signaling promotes resistance to FGFR1 inhibition in squamous-cell lung cancer |
| title_full | Activation of CD44/PAK1/AKT signaling promotes resistance to FGFR1 inhibition in squamous-cell lung cancer |
| title_fullStr | Activation of CD44/PAK1/AKT signaling promotes resistance to FGFR1 inhibition in squamous-cell lung cancer |
| title_full_unstemmed | Activation of CD44/PAK1/AKT signaling promotes resistance to FGFR1 inhibition in squamous-cell lung cancer |
| title_short | Activation of CD44/PAK1/AKT signaling promotes resistance to FGFR1 inhibition in squamous-cell lung cancer |
| title_sort | activation of cd44 pak1 akt signaling promotes resistance to fgfr1 inhibition in squamous cell lung cancer |
| url | https://doi.org/10.1038/s41698-022-00296-2 |
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