biostudies-literatureHuisman DHNational Cancer Institute (NCI)U.S. Department of DefenseU.S. Department of Defense (DOD)National Cancer InstituteNCI NIH HHSNebraska Department of Health and Human Services (Nebraska DHHS)Nebraska Department of Health and Human ServicesNational Institute of General Medical SciencesNIGMS NIH HHSNational Institute of General Medical Sciences (NIGMS)640-652https://www.ebi.ac.uk/biostudies/studies/S-EPMC12221803biostudies-literatureUnknown23(7)Small cell lung carcinoma (SCLC) tumors are heterogeneous, with a subpopulation of cells primed for tumor initiation. In this study, we show that kinase suppressor of Ras 2 (KSR2) promotes the self-renewal and clonogenicity of SCLC cells. KSR2 is a molecular scaffold that promotes Raf/MEK/ERK signaling. KSR2 is preferentially expressed in the ASCL1 subtype of SCLC (SCLC-A) tumors and is expressed in pulmonary neuroendocrine cells, one of the identified cells of origin for SCLC-A tumors. The expression of KSR2 in SCLC and pulmonary neuroendocrine cells was previously unrecognized and serves as a novel model for understanding the role of KSR2-dependent signaling in normal and malignant tissues. Disruption of KSR2 in SCLC-A cell lines inhibits the colony-forming ability of tumor-propagating cMolecular cancer research : MCRKSR2 Promotes Self-Renewal and Clonogenicity of Small Cell Lung Carcinoma.PMC12221803P30 CA036727F30 CA268766U24 CA213274NIH GM121316 and CA277495P20 GM121316LC210123LB 506R01 CA277495P50 CA070907P20 GM103427P30CA036727R21CA256638R21 CA256638U24CA213274Huisman DHSkupa SChatterjee DMinna JDSvoboda RAIreland ASLewis REVieira HMFrodyma DEOliver TGAskew JWGirard LKareta MSFisher KWfalseKSR2 Promotes Self-Renewal and Clonogenicity of Small Cell Lung Carcinoma.Small cell lung carcinoma (SCLC) tumors are heterogeneous, with a subpopulation of cells primed for tumor initiation. In this study, we show that kinase suppressor of Ras 2 (KSR2) promotes the self-renewal and clonogenicity of SCLC cells. KSR2 is a molecular scaffold that promotes Raf/MEK/ERK signaling. KSR2 is preferentially expressed in the ASCL1 subtype of SCLC (SCLC-A) tumors and is expressed in pulmonary neuroendocrine cells, one of the identified cells of origin for SCLC-A tumors. The expression of KSR2 in SCLC and pulmonary neuroendocrine cells was previously unrecognized and serves as a novel model for understanding the role of KSR2-dependent signaling in normal and malignant tissues. Disruption of KSR2 in SCLC-A cell lines inhibits the colony-forming ability of tumor-propagating c2025-01-01T00:00:00Z2025 Jul2026-06-06T09:00:36.981Z2026-05-28T03:10:49.635ZS-EPMC122218034006351510.1158/1541-7786.mcr-24-054610.1158/1541-7786.MCR-24-0546