期刊
ONCOTARGET
卷 8, 期 43, 页码 73745-73756出版社
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.20572
关键词
INSM1; YAP1; small cell; RB1; CDK4/6
资金
- University Hospitals Seidman Cancer Center
- Case School of Medicine
- Tissue Resources Core
- Biostatistics & Bioinformatics Core of the Case Comprehensive Cancer Center [National Institute of Health] [P30 CA43703]
The majority of small cell lung cancer (SCLC) patients demonstrate initial chemosensitivity, whereas a distinct subgroup of SCLC patients, termed chemo-refractory, do not respond to treatment. There is little understanding of how to distinguish these patients prior to disease treatment. Here we used gene expression profiling to stratify SCLC into subgroups and characterized a molecular phenotype that may identify, in part, chemo-refractive SCLC patients. Two subgroups of SCLC were identified in both cell lines and tumors by the reciprocal expression of two genes; INSM1, a neuroendocrine transcription factor, and YAP1, a key mediator of the Hippo pathway. The great majority of tumors expressed INSM1, which was prognostic for increased progression-free survival and associated with chemo-sensitivity in cell lines. YAP1 is expressed in a minority of SCLC tumors and was shown in cell lines to be downstream of the retinoblastoma protein (RB1) and associated with decreased drug sensitivity. RB1 expression in SCLC cell lines sensitizes them to CDK4/6 inhibitors. Wild-type RB1 mutation status, used as a surrogate marker of YAP1 expression, was prognostic for decreased patient survival and increased chemo-refractory tumor response. Thus, the reciprocal expression of INSM1 and YAP1 appears to stratify SCLC into distinct subgroups and may be useful, along with RB1 mutation status, to identify chemorefractory SCLC patients.
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