Targeting the Fibroblast Growth Factor Receptor (FGFR) Family in Lung Cancer
Lung cancer is the most common cause of cancer-related deaths globally. Genetic alterations, such as amplifications, mutations and translocations in the fibroblast growth factor receptor (FGFR) family have been found in non-small cell lung cancer (NSCLC) where they have a role in cancer initiation a...
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| Format: | Article |
| Language: | English |
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MDPI AG
2021-05-01
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| Series: | Cells |
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| Online Access: | https://www.mdpi.com/2073-4409/10/5/1154 |
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| author | Laura Pacini Andrew D. Jenks Nadia Carvalho Lima Paul H. Huang |
| author_facet | Laura Pacini Andrew D. Jenks Nadia Carvalho Lima Paul H. Huang |
| author_sort | Laura Pacini |
| collection | DOAJ |
| description | Lung cancer is the most common cause of cancer-related deaths globally. Genetic alterations, such as amplifications, mutations and translocations in the fibroblast growth factor receptor (FGFR) family have been found in non-small cell lung cancer (NSCLC) where they have a role in cancer initiation and progression. <i>FGFR</i> aberrations have also been identified as key compensatory bypass mechanisms of resistance to targeted therapy against mutant epidermal growth factor receptor (EGFR) and mutant Kirsten rat sarcoma 2 viral oncogene homolog (KRAS) in lung cancer. Targeting FGFR is, therefore, of clinical relevance for this cancer type, and several selective and nonselective FGFR inhibitors have been developed in recent years. Despite promising preclinical data, clinical trials have largely shown low efficacy of these agents in lung cancer patients with <i>FGFR</i> alterations. Preclinical studies have highlighted the emergence of multiple intrinsic and acquired resistance mechanisms to FGFR tyrosine kinase inhibitors, which include on-target <i>FGFR</i> gatekeeper mutations and activation of bypass signalling pathways and alternative receptor tyrosine kinases. Here, we review the landscape of FGFR aberrations in lung cancer and the array of targeted therapies under clinical evaluation. We also discuss the current understanding of the mechanisms of resistance to FGFR-targeting compounds and therapeutic strategies to circumvent resistance. Finally, we highlight our perspectives on the development of new biomarkers for stratification and prediction of FGFR inhibitor response to enable personalisation of treatment in patients with lung cancer. |
| first_indexed | 2024-03-10T11:33:38Z |
| format | Article |
| id | doaj.art-6234416d3b7d4859aca65c36e1e455ea |
| institution | Directory Open Access Journal |
| issn | 2073-4409 |
| language | English |
| last_indexed | 2024-03-10T11:33:38Z |
| publishDate | 2021-05-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cells |
| spelling | doaj.art-6234416d3b7d4859aca65c36e1e455ea2023-11-21T19:03:17ZengMDPI AGCells2073-44092021-05-01105115410.3390/cells10051154Targeting the Fibroblast Growth Factor Receptor (FGFR) Family in Lung CancerLaura Pacini0Andrew D. Jenks1Nadia Carvalho Lima2Paul H. Huang3Division of Molecular Pathology, The Institute of Cancer Research, London SM2 5NG, UKDivision of Molecular Pathology, The Institute of Cancer Research, London SM2 5NG, UKDivision of Molecular Pathology, The Institute of Cancer Research, London SM2 5NG, UKDivision of Molecular Pathology, The Institute of Cancer Research, London SM2 5NG, UKLung cancer is the most common cause of cancer-related deaths globally. Genetic alterations, such as amplifications, mutations and translocations in the fibroblast growth factor receptor (FGFR) family have been found in non-small cell lung cancer (NSCLC) where they have a role in cancer initiation and progression. <i>FGFR</i> aberrations have also been identified as key compensatory bypass mechanisms of resistance to targeted therapy against mutant epidermal growth factor receptor (EGFR) and mutant Kirsten rat sarcoma 2 viral oncogene homolog (KRAS) in lung cancer. Targeting FGFR is, therefore, of clinical relevance for this cancer type, and several selective and nonselective FGFR inhibitors have been developed in recent years. Despite promising preclinical data, clinical trials have largely shown low efficacy of these agents in lung cancer patients with <i>FGFR</i> alterations. Preclinical studies have highlighted the emergence of multiple intrinsic and acquired resistance mechanisms to FGFR tyrosine kinase inhibitors, which include on-target <i>FGFR</i> gatekeeper mutations and activation of bypass signalling pathways and alternative receptor tyrosine kinases. Here, we review the landscape of FGFR aberrations in lung cancer and the array of targeted therapies under clinical evaluation. We also discuss the current understanding of the mechanisms of resistance to FGFR-targeting compounds and therapeutic strategies to circumvent resistance. Finally, we highlight our perspectives on the development of new biomarkers for stratification and prediction of FGFR inhibitor response to enable personalisation of treatment in patients with lung cancer.https://www.mdpi.com/2073-4409/10/5/1154FGFRlung cancertyrosine kinase inhibitorsdrug resistance |
| spellingShingle | Laura Pacini Andrew D. Jenks Nadia Carvalho Lima Paul H. Huang Targeting the Fibroblast Growth Factor Receptor (FGFR) Family in Lung Cancer Cells FGFR lung cancer tyrosine kinase inhibitors drug resistance |
| title | Targeting the Fibroblast Growth Factor Receptor (FGFR) Family in Lung Cancer |
| title_full | Targeting the Fibroblast Growth Factor Receptor (FGFR) Family in Lung Cancer |
| title_fullStr | Targeting the Fibroblast Growth Factor Receptor (FGFR) Family in Lung Cancer |
| title_full_unstemmed | Targeting the Fibroblast Growth Factor Receptor (FGFR) Family in Lung Cancer |
| title_short | Targeting the Fibroblast Growth Factor Receptor (FGFR) Family in Lung Cancer |
| title_sort | targeting the fibroblast growth factor receptor fgfr family in lung cancer |
| topic | FGFR lung cancer tyrosine kinase inhibitors drug resistance |
| url | https://www.mdpi.com/2073-4409/10/5/1154 |
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