The function and therapeutic targeting of anaplastic lymphoma kinase (ALK) in non-small cell lung cancer (NSCLC)
Abstract Lung cancer is the leading cause of death by cancer in North America. A decade ago, genomic rearrangements in the anaplastic lymphoma kinase (ALK) receptor tyrosine kinase were identified in a subset of non-small cell lung carcinoma (NSCLC) patients. Soon after, crizotinib, a small molecule...
| Main Authors: | , , , |
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| Format: | Article |
| Language: | English |
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BMC
2018-02-01
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| Series: | Molecular Cancer |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s12943-018-0810-4 |
| _version_ | 1819093362057150464 |
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| author | Brandon Golding Anita Luu Robert Jones Alicia M. Viloria-Petit |
| author_facet | Brandon Golding Anita Luu Robert Jones Alicia M. Viloria-Petit |
| author_sort | Brandon Golding |
| collection | DOAJ |
| description | Abstract Lung cancer is the leading cause of death by cancer in North America. A decade ago, genomic rearrangements in the anaplastic lymphoma kinase (ALK) receptor tyrosine kinase were identified in a subset of non-small cell lung carcinoma (NSCLC) patients. Soon after, crizotinib, a small molecule ATP-competitive ALK inhibitor was proven to be more effective than chemotherapy in ALK-positive NSCLC patients. Crizotinib and two other ATP-competitive ALK inhibitors, ceritinib and alectinib, are approved for use as a first-line therapy in these patients, where ALK rearrangement is currently diagnosed by immunohistochemistry and in situ hybridization. The clinical success of these three ALK inhibitors has led to the development of next-generation ALK inhibitors with even greater potency and selectivity. However, patients inevitably develop resistance to ALK inhibitors leading to tumor relapse that commonly manifests in the form of brain metastasis. Several new approaches aim to overcome the various mechanisms of resistance that develop in ALK-positive NSCLC including the knowledge-based alternate and successive use of different ALK inhibitors, as well as combined therapies targeting ALK plus alternative signaling pathways. Key issues to resolve for the optimal implementation of established and emerging treatment modalities for ALK-rearranged NSCLC therapy include the high cost of the targeted inhibitors and the potential of exacerbated toxicities with combination therapies. |
| first_indexed | 2024-12-21T23:10:18Z |
| format | Article |
| id | doaj.art-5fdf1931d0e54923afd0c1b6155530b2 |
| institution | Directory Open Access Journal |
| issn | 1476-4598 |
| language | English |
| last_indexed | 2024-12-21T23:10:18Z |
| publishDate | 2018-02-01 |
| publisher | BMC |
| record_format | Article |
| series | Molecular Cancer |
| spelling | doaj.art-5fdf1931d0e54923afd0c1b6155530b22022-12-21T18:47:04ZengBMCMolecular Cancer1476-45982018-02-0117111510.1186/s12943-018-0810-4The function and therapeutic targeting of anaplastic lymphoma kinase (ALK) in non-small cell lung cancer (NSCLC)Brandon Golding0Anita Luu1Robert Jones2Alicia M. Viloria-Petit3Department of Biomedical Sciences, Ontario Veterinary College, University of GuelphDepartment of Biomedical Sciences, Ontario Veterinary College, University of GuelphDepartment of Biomedical Sciences, Ontario Veterinary College, University of GuelphDepartment of Biomedical Sciences, Ontario Veterinary College, University of GuelphAbstract Lung cancer is the leading cause of death by cancer in North America. A decade ago, genomic rearrangements in the anaplastic lymphoma kinase (ALK) receptor tyrosine kinase were identified in a subset of non-small cell lung carcinoma (NSCLC) patients. Soon after, crizotinib, a small molecule ATP-competitive ALK inhibitor was proven to be more effective than chemotherapy in ALK-positive NSCLC patients. Crizotinib and two other ATP-competitive ALK inhibitors, ceritinib and alectinib, are approved for use as a first-line therapy in these patients, where ALK rearrangement is currently diagnosed by immunohistochemistry and in situ hybridization. The clinical success of these three ALK inhibitors has led to the development of next-generation ALK inhibitors with even greater potency and selectivity. However, patients inevitably develop resistance to ALK inhibitors leading to tumor relapse that commonly manifests in the form of brain metastasis. Several new approaches aim to overcome the various mechanisms of resistance that develop in ALK-positive NSCLC including the knowledge-based alternate and successive use of different ALK inhibitors, as well as combined therapies targeting ALK plus alternative signaling pathways. Key issues to resolve for the optimal implementation of established and emerging treatment modalities for ALK-rearranged NSCLC therapy include the high cost of the targeted inhibitors and the potential of exacerbated toxicities with combination therapies.http://link.springer.com/article/10.1186/s12943-018-0810-4Lung cancerAnaplastic lymphoma kinaseALKMolecular-targeted therapyCell signalling |
| spellingShingle | Brandon Golding Anita Luu Robert Jones Alicia M. Viloria-Petit The function and therapeutic targeting of anaplastic lymphoma kinase (ALK) in non-small cell lung cancer (NSCLC) Molecular Cancer Lung cancer Anaplastic lymphoma kinase ALK Molecular-targeted therapy Cell signalling |
| title | The function and therapeutic targeting of anaplastic lymphoma kinase (ALK) in non-small cell lung cancer (NSCLC) |
| title_full | The function and therapeutic targeting of anaplastic lymphoma kinase (ALK) in non-small cell lung cancer (NSCLC) |
| title_fullStr | The function and therapeutic targeting of anaplastic lymphoma kinase (ALK) in non-small cell lung cancer (NSCLC) |
| title_full_unstemmed | The function and therapeutic targeting of anaplastic lymphoma kinase (ALK) in non-small cell lung cancer (NSCLC) |
| title_short | The function and therapeutic targeting of anaplastic lymphoma kinase (ALK) in non-small cell lung cancer (NSCLC) |
| title_sort | function and therapeutic targeting of anaplastic lymphoma kinase alk in non small cell lung cancer nsclc |
| topic | Lung cancer Anaplastic lymphoma kinase ALK Molecular-targeted therapy Cell signalling |
| url | http://link.springer.com/article/10.1186/s12943-018-0810-4 |
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