MET-Pyk2 Axis Mediates Acquired Resistance to FGFR Inhibition in Cancer Cells
Deregulation of fibroblast growth factor receptors (FGFRs) signaling, as a result of FGFR amplification, chromosomal translocation, or mutations, is involved in both initiation and progression of a wide range of human cancers. Clinical data demonstrating the dependence of cancer cells on FGFRs signa...
| Main Authors: | , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Frontiers Media S.A.
2021-04-01
|
| Series: | Frontiers in Oncology |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/articles/10.3389/fonc.2021.633410/full |
| _version_ | 1828937781608448000 |
|---|---|
| author | Kamila Kitowska Monika Gorska-Arcisz Dima Antoun Izabela Zarczynska Dominika Czaplinska Adrian Szczepaniak Andrzej C. Skladanowski Maciej Wieczorek Aleksandra Stanczak Monika Skupinska Rafal Sadej |
| author_facet | Kamila Kitowska Monika Gorska-Arcisz Dima Antoun Izabela Zarczynska Dominika Czaplinska Adrian Szczepaniak Andrzej C. Skladanowski Maciej Wieczorek Aleksandra Stanczak Monika Skupinska Rafal Sadej |
| author_sort | Kamila Kitowska |
| collection | DOAJ |
| description | Deregulation of fibroblast growth factor receptors (FGFRs) signaling, as a result of FGFR amplification, chromosomal translocation, or mutations, is involved in both initiation and progression of a wide range of human cancers. Clinical data demonstrating the dependence of cancer cells on FGFRs signaling clearly indicate these receptors as the molecular targets of anti-cancer therapies. Despite the increasing number of tyrosine kinase inhibitors (TKIs) being investigated in clinical trials, acquired resistance to these drugs poses a serious therapeutic problem. In this study, we focused on a novel pan-FGFR inhibitor—CPL304110, currently being investigated in phase I clinical trials in adults with advanced solid malignancies. We analyzed the sensitivity of 17 cell lines derived from cancers with aberrant FGFR signaling, i.e. non-small cell lung cancer, gastric and bladder cancer to CPL304110. In order to explore the mechanism of acquired resistance to this FGFR inhibitor, we developed from sensitive cell lines their variants resistant to CPL304110. Herein, for the first time we revealed that the process of acquired resistance to the novel FGFR inhibitor was associated with increased expression of MET in lung, gastric, and bladder cancer cells. Overexpression of MET in NCI-H1703, SNU-16, RT-112 cells as well as treatment with HGF resulted in the impaired response to inhibition of FGFR activity. Moreover, we demonstrated that cells with acquired resistance to FGFR inhibitor as well as cells overexpressing MET displayed enhanced migratory abilities what was accompanied with increased levels of Pyk2 expression. Importantly, inhibition of both MET and Pyk2 activity restored sensitivity to FGFR inhibition in these cells. Our results demonstrate that the HGF/MET-Pyk2 signaling axis confers resistance to the novel FGFR inhibitor, and this mechanism is common for lung, gastric, and bladder cancer cells. Our study suggests that targeting of MET/Pyk2 could be an approach to overcome resistance to FGFR inhibition. |
| first_indexed | 2024-12-14T02:31:23Z |
| format | Article |
| id | doaj.art-b886481cff41457ab09655e07600ec36 |
| institution | Directory Open Access Journal |
| issn | 2234-943X |
| language | English |
| last_indexed | 2024-12-14T02:31:23Z |
| publishDate | 2021-04-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Oncology |
| spelling | doaj.art-b886481cff41457ab09655e07600ec362022-12-21T23:20:15ZengFrontiers Media S.A.Frontiers in Oncology2234-943X2021-04-011110.3389/fonc.2021.633410633410MET-Pyk2 Axis Mediates Acquired Resistance to FGFR Inhibition in Cancer CellsKamila Kitowska0Monika Gorska-Arcisz1Dima Antoun2Izabela Zarczynska3Dominika Czaplinska4Adrian Szczepaniak5Andrzej C. Skladanowski6Maciej Wieczorek7Aleksandra Stanczak8Monika Skupinska9Rafal Sadej10Department of Molecular Enzymology and Oncology, Intercollegiate Faculty of Biotechnology, University of Gdansk and Medical University of Gdansk, Gdansk, PolandDepartment of Molecular Enzymology and Oncology, Intercollegiate Faculty of Biotechnology, University of Gdansk and Medical University of Gdansk, Gdansk, PolandDepartment of Molecular Enzymology and Oncology, Intercollegiate Faculty of Biotechnology, University of Gdansk and Medical University of Gdansk, Gdansk, PolandDepartment of Molecular Enzymology and Oncology, Intercollegiate Faculty of Biotechnology, University of Gdansk and Medical University of Gdansk, Gdansk, PolandDepartment of Molecular Enzymology and Oncology, Intercollegiate Faculty of Biotechnology, University of Gdansk and Medical University of Gdansk, Gdansk, PolandDepartment of Molecular Enzymology and Oncology, Intercollegiate Faculty of Biotechnology, University of Gdansk and Medical University of Gdansk, Gdansk, PolandDepartment of Molecular Enzymology and Oncology, Intercollegiate Faculty of Biotechnology, University of Gdansk and Medical University of Gdansk, Gdansk, PolandInnovative Drugs R&D Department, Celon Pharma, Lomianki/Kielpin, PolandInnovative Drugs R&D Department, Celon Pharma, Lomianki/Kielpin, PolandInnovative Drugs R&D Department, Celon Pharma, Lomianki/Kielpin, PolandDepartment of Molecular Enzymology and Oncology, Intercollegiate Faculty of Biotechnology, University of Gdansk and Medical University of Gdansk, Gdansk, PolandDeregulation of fibroblast growth factor receptors (FGFRs) signaling, as a result of FGFR amplification, chromosomal translocation, or mutations, is involved in both initiation and progression of a wide range of human cancers. Clinical data demonstrating the dependence of cancer cells on FGFRs signaling clearly indicate these receptors as the molecular targets of anti-cancer therapies. Despite the increasing number of tyrosine kinase inhibitors (TKIs) being investigated in clinical trials, acquired resistance to these drugs poses a serious therapeutic problem. In this study, we focused on a novel pan-FGFR inhibitor—CPL304110, currently being investigated in phase I clinical trials in adults with advanced solid malignancies. We analyzed the sensitivity of 17 cell lines derived from cancers with aberrant FGFR signaling, i.e. non-small cell lung cancer, gastric and bladder cancer to CPL304110. In order to explore the mechanism of acquired resistance to this FGFR inhibitor, we developed from sensitive cell lines their variants resistant to CPL304110. Herein, for the first time we revealed that the process of acquired resistance to the novel FGFR inhibitor was associated with increased expression of MET in lung, gastric, and bladder cancer cells. Overexpression of MET in NCI-H1703, SNU-16, RT-112 cells as well as treatment with HGF resulted in the impaired response to inhibition of FGFR activity. Moreover, we demonstrated that cells with acquired resistance to FGFR inhibitor as well as cells overexpressing MET displayed enhanced migratory abilities what was accompanied with increased levels of Pyk2 expression. Importantly, inhibition of both MET and Pyk2 activity restored sensitivity to FGFR inhibition in these cells. Our results demonstrate that the HGF/MET-Pyk2 signaling axis confers resistance to the novel FGFR inhibitor, and this mechanism is common for lung, gastric, and bladder cancer cells. Our study suggests that targeting of MET/Pyk2 could be an approach to overcome resistance to FGFR inhibition.https://www.frontiersin.org/articles/10.3389/fonc.2021.633410/fullFGFRMETPyk2acquired resistancecancer |
| spellingShingle | Kamila Kitowska Monika Gorska-Arcisz Dima Antoun Izabela Zarczynska Dominika Czaplinska Adrian Szczepaniak Andrzej C. Skladanowski Maciej Wieczorek Aleksandra Stanczak Monika Skupinska Rafal Sadej MET-Pyk2 Axis Mediates Acquired Resistance to FGFR Inhibition in Cancer Cells Frontiers in Oncology FGFR MET Pyk2 acquired resistance cancer |
| title | MET-Pyk2 Axis Mediates Acquired Resistance to FGFR Inhibition in Cancer Cells |
| title_full | MET-Pyk2 Axis Mediates Acquired Resistance to FGFR Inhibition in Cancer Cells |
| title_fullStr | MET-Pyk2 Axis Mediates Acquired Resistance to FGFR Inhibition in Cancer Cells |
| title_full_unstemmed | MET-Pyk2 Axis Mediates Acquired Resistance to FGFR Inhibition in Cancer Cells |
| title_short | MET-Pyk2 Axis Mediates Acquired Resistance to FGFR Inhibition in Cancer Cells |
| title_sort | met pyk2 axis mediates acquired resistance to fgfr inhibition in cancer cells |
| topic | FGFR MET Pyk2 acquired resistance cancer |
| url | https://www.frontiersin.org/articles/10.3389/fonc.2021.633410/full |
| work_keys_str_mv | AT kamilakitowska metpyk2axismediatesacquiredresistancetofgfrinhibitionincancercells AT monikagorskaarcisz metpyk2axismediatesacquiredresistancetofgfrinhibitionincancercells AT dimaantoun metpyk2axismediatesacquiredresistancetofgfrinhibitionincancercells AT izabelazarczynska metpyk2axismediatesacquiredresistancetofgfrinhibitionincancercells AT dominikaczaplinska metpyk2axismediatesacquiredresistancetofgfrinhibitionincancercells AT adrianszczepaniak metpyk2axismediatesacquiredresistancetofgfrinhibitionincancercells AT andrzejcskladanowski metpyk2axismediatesacquiredresistancetofgfrinhibitionincancercells AT maciejwieczorek metpyk2axismediatesacquiredresistancetofgfrinhibitionincancercells AT aleksandrastanczak metpyk2axismediatesacquiredresistancetofgfrinhibitionincancercells AT monikaskupinska metpyk2axismediatesacquiredresistancetofgfrinhibitionincancercells AT rafalsadej metpyk2axismediatesacquiredresistancetofgfrinhibitionincancercells |