| pubmed-article:21502504 | rdf:type | pubmed:Citation | lld:pubmed |
| pubmed-article:21502504 | lifeskim:mentions | umls-concept:C0029016 | lld:lifeskim |
| pubmed-article:21502504 | lifeskim:mentions | umls-concept:C0007131 | lld:lifeskim |
| pubmed-article:21502504 | lifeskim:mentions | umls-concept:C0332466 | lld:lifeskim |
| pubmed-article:21502504 | lifeskim:mentions | umls-concept:C0679199 | lld:lifeskim |
| pubmed-article:21502504 | lifeskim:mentions | umls-concept:C0683598 | lld:lifeskim |
| pubmed-article:21502504 | lifeskim:mentions | umls-concept:C0302350 | lld:lifeskim |
| pubmed-article:21502504 | pubmed:issue | 18 | lld:pubmed |
| pubmed-article:21502504 | pubmed:dateCreated | 2011-5-4 | lld:pubmed |
| pubmed-article:21502504 | pubmed:abstractText | 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 ?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. | lld:pubmed |
| pubmed-article:21502504 | pubmed:grant | http://linkedlifedata.com/r... | lld:pubmed |
| pubmed-article:21502504 | pubmed:language | eng | lld:pubmed |
| pubmed-article:21502504 | pubmed:journal | http://linkedlifedata.com/r... | lld:pubmed |
| pubmed-article:21502504 | pubmed:citationSubset | IM | lld:pubmed |
| pubmed-article:21502504 | pubmed:chemical | http://linkedlifedata.com/r... | lld:pubmed |
| pubmed-article:21502504 | pubmed:chemical | http://linkedlifedata.com/r... | lld:pubmed |
| pubmed-article:21502504 | pubmed:chemical | http://linkedlifedata.com/r... | lld:pubmed |
| pubmed-article:21502504 | pubmed:chemical | http://linkedlifedata.com/r... | lld:pubmed |
| pubmed-article:21502504 | pubmed:chemical | http://linkedlifedata.com/r... | lld:pubmed |
| pubmed-article:21502504 | pubmed:chemical | http://linkedlifedata.com/r... | lld:pubmed |
| pubmed-article:21502504 | pubmed:chemical | http://linkedlifedata.com/r... | lld:pubmed |
| pubmed-article:21502504 | pubmed:chemical | http://linkedlifedata.com/r... | lld:pubmed |
| pubmed-article:21502504 | pubmed:chemical | http://linkedlifedata.com/r... | lld:pubmed |
| pubmed-article:21502504 | pubmed:chemical | http://linkedlifedata.com/r... | lld:pubmed |
| pubmed-article:21502504 | pubmed:status | MEDLINE | lld:pubmed |
| pubmed-article:21502504 | pubmed:month | May | lld:pubmed |
| pubmed-article:21502504 | pubmed:issn | 1091-6490 | lld:pubmed |
| pubmed-article:21502504 | pubmed:author | pubmed-author:RiveraVictor... | lld:pubmed |
| pubmed-article:21502504 | pubmed:author | pubmed-author:EbiHiromichiH | lld:pubmed |
| pubmed-article:21502504 | pubmed:author | pubmed-author:KatayamaRyohe... | lld:pubmed |
| pubmed-article:21502504 | pubmed:author | pubmed-author:ShakespeareWi... | lld:pubmed |
| pubmed-article:21502504 | pubmed:author | pubmed-author:ShawAlice TAT | lld:pubmed |
| pubmed-article:21502504 | pubmed:author | pubmed-author:IafrateA... | lld:pubmed |
| pubmed-article:21502504 | pubmed:author | pubmed-author:EngelmanJeffr... | lld:pubmed |
| pubmed-article:21502504 | pubmed:author | pubmed-author:LifshitsEugen... | lld:pubmed |
| pubmed-article:21502504 | pubmed:author | pubmed-author:BenesCyrilC | lld:pubmed |
| pubmed-article:21502504 | pubmed:author | pubmed-author:KhanTahsin... | lld:pubmed |
| pubmed-article:21502504 | pubmed:issnType | Electronic | lld:pubmed |
| pubmed-article:21502504 | pubmed:day | 3 | lld:pubmed |
| pubmed-article:21502504 | pubmed:volume | 108 | lld:pubmed |
| pubmed-article:21502504 | pubmed:owner | NLM | lld:pubmed |
| pubmed-article:21502504 | pubmed:authorsComplete | Y | lld:pubmed |
| pubmed-article:21502504 | pubmed:pagination | 7535-40 | lld:pubmed |
| pubmed-article:21502504 | pubmed:dateRevised | 2011-11-3 | lld:pubmed |
| pubmed-article:21502504 | pubmed:meshHeading | pubmed-meshheading:21502504... | lld:pubmed |
| pubmed-article:21502504 | pubmed:meshHeading | pubmed-meshheading:21502504... | lld:pubmed |
| pubmed-article:21502504 | pubmed:meshHeading | pubmed-meshheading:21502504... | lld:pubmed |
| pubmed-article:21502504 | pubmed:meshHeading | pubmed-meshheading:21502504... | lld:pubmed |
| pubmed-article:21502504 | pubmed:meshHeading | pubmed-meshheading:21502504... | lld:pubmed |
| pubmed-article:21502504 | pubmed:meshHeading | pubmed-meshheading:21502504... | lld:pubmed |
| pubmed-article:21502504 | pubmed:meshHeading | pubmed-meshheading:21502504... | lld:pubmed |
| pubmed-article:21502504 | pubmed:meshHeading | pubmed-meshheading:21502504... | lld:pubmed |
| pubmed-article:21502504 | pubmed:meshHeading | pubmed-meshheading:21502504... | lld:pubmed |
| pubmed-article:21502504 | pubmed:meshHeading | pubmed-meshheading:21502504... | lld:pubmed |
| pubmed-article:21502504 | pubmed:meshHeading | pubmed-meshheading:21502504... | lld:pubmed |
| pubmed-article:21502504 | pubmed:meshHeading | pubmed-meshheading:21502504... | lld:pubmed |
| pubmed-article:21502504 | pubmed:meshHeading | pubmed-meshheading:21502504... | lld:pubmed |
| pubmed-article:21502504 | pubmed:meshHeading | pubmed-meshheading:21502504... | lld:pubmed |
| pubmed-article:21502504 | pubmed:meshHeading | pubmed-meshheading:21502504... | lld:pubmed |
| pubmed-article:21502504 | pubmed:meshHeading | pubmed-meshheading:21502504... | lld:pubmed |
| pubmed-article:21502504 | pubmed:meshHeading | pubmed-meshheading:21502504... | lld:pubmed |
| pubmed-article:21502504 | pubmed:meshHeading | pubmed-meshheading:21502504... | lld:pubmed |
| pubmed-article:21502504 | pubmed:meshHeading | pubmed-meshheading:21502504... | lld:pubmed |
| pubmed-article:21502504 | pubmed:meshHeading | pubmed-meshheading:21502504... | lld:pubmed |
| pubmed-article:21502504 | pubmed:meshHeading | pubmed-meshheading:21502504... | lld:pubmed |
| pubmed-article:21502504 | pubmed:meshHeading | pubmed-meshheading:21502504... | lld:pubmed |
| pubmed-article:21502504 | pubmed:meshHeading | pubmed-meshheading:21502504... | lld:pubmed |
| pubmed-article:21502504 | pubmed:meshHeading | pubmed-meshheading:21502504... | lld:pubmed |
| pubmed-article:21502504 | pubmed:meshHeading | pubmed-meshheading:21502504... | lld:pubmed |
| pubmed-article:21502504 | pubmed:year | 2011 | lld:pubmed |
| pubmed-article:21502504 | pubmed:articleTitle | Therapeutic strategies to overcome crizotinib resistance in non-small cell lung cancers harboring the fusion oncogene EML4-ALK. | lld:pubmed |
| pubmed-article:21502504 | pubmed:affiliation | Massachusetts General Hospital Cancer Center, Boston, MA 02129, USA. | lld:pubmed |
| pubmed-article:21502504 | pubmed:publicationType | Journal Article | lld:pubmed |
| pubmed-article:21502504 | pubmed:publicationType | Research Support, Non-U.S. Gov't | lld:pubmed |
| pubmed-article:21502504 | pubmed:publicationType | Research Support, N.I.H., Extramural | lld:pubmed |
