Therapeutic strategies to overcome crizotinib resistance in non-small cell lung cancers harboring the fusion oncogene EML4-ALK
The echinoderm microtubule-associated protein-like 4 (EML4)-anaplastic lymphoma kinase (ALK) fusion oncogene represents a molecular target in a small subset of non-small cell lung cancers (NSCLCs). This fusion leads to constitutive ALK activation with potent transforming activity. In a pivotal phase...
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| Format: | Article |
| Language: | en_US |
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National Academy of Sciences
2011
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| Online Access: | http://hdl.handle.net/1721.1/67357 |
| _version_ | 1826195462592397312 |
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| author | Katayama, Ryohei Benes, Cyril H. Lifshits, Eugene Ebi, Hiromichi Rivera, Victor M. Shakespeare, William C. Iafrate, A. John Engelman, Jeffrey A. Shaw, Alice |
| author2 | Koch Institute for Integrative Cancer Research at MIT |
| author_facet | Koch Institute for Integrative Cancer Research at MIT Katayama, Ryohei Benes, Cyril H. Lifshits, Eugene Ebi, Hiromichi Rivera, Victor M. Shakespeare, William C. Iafrate, A. John Engelman, Jeffrey A. Shaw, Alice |
| author_sort | Katayama, Ryohei |
| collection | MIT |
| description | The echinoderm microtubule-associated protein-like 4 (EML4)-anaplastic lymphoma kinase (ALK) fusion oncogene represents a molecular target in a small subset of non-small cell lung cancers (NSCLCs). This fusion leads to constitutive ALK activation with potent transforming activity. In a pivotal phase 1 clinical trial, the ALK tyrosine kinase inhibitor (TKI) crizotinib (PF-02341066) demonstrated impressive antitumor activity in the majority of patients with NSCLC harboring ALK fusions. However, despite these remarkable initial responses, cancers eventually develop resistance to crizotinib, usually within 1 y, thereby limiting the potential clinical benefit. To determine how cancers acquire resistance to ALK inhibitors, we established a model of acquired resistance to crizotinib by exposing a highly sensitive EML4-ALK–positive NSCLC cell line to increasing doses of crizotinib until resistance emerged. We found that cells resistant to intermediate doses of crizotinib developed amplification of the EML4-ALK gene. Cells resistant to higher doses (1 μM) also developed a gatekeeper mutation, L1196M, within the kinase domain, rendering EML4-ALK insensitive to crizotinib. This gatekeeper mutation was readily detected using a unique and highly sensitive allele-specific PCR assay. Although crizotinib was ineffectual against EML4-ALK harboring the gatekeeper mutation, we observed that two structurally different ALK inhibitors, NVP-TAE684 and AP26113, were highly active against the resistant cancer cells in vitro and in vivo. Furthermore, these resistant cells remained highly sensitive to the Hsp90 inhibitor 17-AAG. Thus, we have developed a model of acquired resistance to ALK inhibitors and have shown that second-generation ALK TKIs or Hsp90 inhibitors are effective in treating crizotinib-resistant tumors harboring secondary gatekeeper mutations. |
| first_indexed | 2024-09-23T10:13:03Z |
| format | Article |
| id | mit-1721.1/67357 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T10:13:03Z |
| publishDate | 2011 |
| publisher | National Academy of Sciences |
| record_format | dspace |
| spelling | mit-1721.1/673572022-09-26T16:29:51Z Therapeutic strategies to overcome crizotinib resistance in non-small cell lung cancers harboring the fusion oncogene EML4-ALK Katayama, Ryohei Benes, Cyril H. Lifshits, Eugene Ebi, Hiromichi Rivera, Victor M. Shakespeare, William C. Iafrate, A. John Engelman, Jeffrey A. Shaw, Alice Koch Institute for Integrative Cancer Research at MIT Shaw, Alice Shaw, Alice The echinoderm microtubule-associated protein-like 4 (EML4)-anaplastic lymphoma kinase (ALK) fusion oncogene represents a molecular target in a small subset of non-small cell lung cancers (NSCLCs). This fusion leads to constitutive ALK activation with potent transforming activity. In a pivotal phase 1 clinical trial, the ALK tyrosine kinase inhibitor (TKI) crizotinib (PF-02341066) demonstrated impressive antitumor activity in the majority of patients with NSCLC harboring ALK fusions. However, despite these remarkable initial responses, cancers eventually develop resistance to crizotinib, usually within 1 y, thereby limiting the potential clinical benefit. To determine how cancers acquire resistance to ALK inhibitors, we established a model of acquired resistance to crizotinib by exposing a highly sensitive EML4-ALK–positive NSCLC cell line to increasing doses of crizotinib until resistance emerged. We found that cells resistant to intermediate doses of crizotinib developed amplification of the EML4-ALK gene. Cells resistant to higher doses (1 μM) also developed a gatekeeper mutation, L1196M, within the kinase domain, rendering EML4-ALK insensitive to crizotinib. This gatekeeper mutation was readily detected using a unique and highly sensitive allele-specific PCR assay. Although crizotinib was ineffectual against EML4-ALK harboring the gatekeeper mutation, we observed that two structurally different ALK inhibitors, NVP-TAE684 and AP26113, were highly active against the resistant cancer cells in vitro and in vivo. Furthermore, these resistant cells remained highly sensitive to the Hsp90 inhibitor 17-AAG. Thus, we have developed a model of acquired resistance to ALK inhibitors and have shown that second-generation ALK TKIs or Hsp90 inhibitors are effective in treating crizotinib-resistant tumors harboring secondary gatekeeper mutations. The V Foundation for Cancer Research Translational Grant Charles W. and Jennifer C. Johnson Koch Institute Clinical Investigator Award National Institutes of Health (NIH) (Grant CA120060-01) Sig Adler Lung Cancer Research Fund Massachusetts General Hospital Japan Society for the Promotion of Science 2011-12-02T19:46:27Z 2011-12-02T19:46:27Z 2011-04 2010-12 Article http://purl.org/eprint/type/JournalArticle 0027-8424 1091-6490 http://hdl.handle.net/1721.1/67357 Katayama, R. et al. “Therapeutic strategies to overcome crizotinib resistance in non-small cell lung cancers harboring the fusion oncogene EML4-ALK.” Proceedings of the National Academy of Sciences 108 (2011): 7535-7540. Web. 2 Dec. 2011. © 2011 New York Academy of Sciences en_US http://dx.doi.org/10.1073/pnas.1019559108 Proceedings of the National Academy of Sciences of the United States of America Article is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use. application/pdf National Academy of Sciences PNAS |
| spellingShingle | Katayama, Ryohei Benes, Cyril H. Lifshits, Eugene Ebi, Hiromichi Rivera, Victor M. Shakespeare, William C. Iafrate, A. John Engelman, Jeffrey A. Shaw, Alice Therapeutic strategies to overcome crizotinib resistance in non-small cell lung cancers harboring the fusion oncogene EML4-ALK |
| title | Therapeutic strategies to overcome crizotinib resistance in non-small cell lung cancers harboring the fusion oncogene EML4-ALK |
| title_full | Therapeutic strategies to overcome crizotinib resistance in non-small cell lung cancers harboring the fusion oncogene EML4-ALK |
| title_fullStr | Therapeutic strategies to overcome crizotinib resistance in non-small cell lung cancers harboring the fusion oncogene EML4-ALK |
| title_full_unstemmed | Therapeutic strategies to overcome crizotinib resistance in non-small cell lung cancers harboring the fusion oncogene EML4-ALK |
| title_short | Therapeutic strategies to overcome crizotinib resistance in non-small cell lung cancers harboring the fusion oncogene EML4-ALK |
| title_sort | therapeutic strategies to overcome crizotinib resistance in non small cell lung cancers harboring the fusion oncogene eml4 alk |
| url | http://hdl.handle.net/1721.1/67357 |
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