Reciprocal expression of INSM1 and YAP1 defines subgroups in small cell lung cancer

Abstract

// Karen McColl 1 , Gary Wildey 1 , Nneha Sakre 1 , Mary Beth Lipka 1 , Mohadese Behtaj 2 , Adam Kresak 3 , Yanwen Chen 4 , Michael Yang 2 , Vamsidhar Velcheti 5 , Pingfu Fu 4 and Afshin Dowlati 6 1 Division of Hematology and Oncology, Case Western Reserve University, Cleveland, OH, USA 2 Department of Pathology, University Hospitals Cleveland Medical Center, Cleveland, OH, USA 3 Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH, USA 4 Department of Population and Quantitative Health Sciences, Case Western Reserve University, Cleveland, OH, USA 5 Division of Hematology and Oncology, Cleveland Clinic Foundation, Cleveland, OH, USA 6 Division of Hematology and Oncology, Case Western Reserve University, University Hospitals Seidman Cancer Center, Cleveland, OH, USA Correspondence to: Afshin Dowlati, email: // Keywords : INSM1, YAP1, small cell, RB1, CDK4/6 Received : July 28, 2017 Accepted : August 03, 2017 Published : August 28, 2017 Abstract The majority of small cell lung cancer (SCLC) patients demonstrate initial chemo-sensitivity, 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 chemo-refractory SCLC patients.