Journal article
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 - PNAS, Vol.108(18), pp.7535-7540
05/03/2011
DOI: 10.1073/pnas.1019559108
PMCID: PMC3088626
PMID: 21502504
Abstract
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 mu M) 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.
Details
- Title: Subtitle
- Therapeutic strategies to overcome crizotinib resistance in non-small cell lung cancers harboring the fusion oncogene EML4-ALK
- Creators
- Ryohei Katayama - Harvard UniversityTahsin M. Khan - Massachusetts General HospitalCyril Benes - Harvard UniversityEugene Lifshits - Massachusetts General HospitalHiromichi Ebi - Harvard UniversityVictor M. Rivera - Ariadne Diagnostics (United States)William C. Shakespeare - Ariadne Diagnostics (United States)A. John Iafrate - Massachusetts General HospitalJeffrey A. Engelman - Harvard UniversityAlice T. Shaw - Harvard University
- Resource Type
- Journal article
- Publication Details
- Proceedings of the National Academy of Sciences - PNAS, Vol.108(18), pp.7535-7540
- DOI
- 10.1073/pnas.1019559108
- PMID
- 21502504
- PMCID
- PMC3088626
- NLM abbreviation
- Proc Natl Acad Sci U S A
- ISSN
- 0027-8424
- eISSN
- 1091-6490
- Publisher
- Natl Acad Sciences
- Number of pages
- 6
- Grant note
- Massachusetts General Hospital Ministry of Education, Culture, Sports, Science, and Technology of Japan; Ministry of Education, Culture, Sports, Science and Technology, Japan (MEXT) CA120060-01 / National Institutes of Health; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA Sig Adler Lung Cancer Research Fund V Foundation for Cancer Research Charles W. and Jennifer C. Johnson Koch Institute
- Language
- English
- Date published
- 05/03/2011
- Academic Unit
- Surgery
- Record Identifier
- 9985224413202771
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