Kinase Suppressor of Ras 2 promotes self-renewal and clonogenicity of small-cell lung carcinoma

Abstract

Tumor propagating cells (TPCs) make up a small proportion of tumor cells responsible for self-renewal and long-term propagation of small-cell lung carcinoma (SCLC) tumors. Here, we show that Kinase Suppressor of Ras 2 (KSR2) is an important regulator of the self-renewing and clonogenic properties of SCLC cells. KSR2 is a molecular scaffold which promotes Raf/MEK/ERK signaling and AMPK signaling in SCLC. KSR2 is preferentially expressed in the ASCL1 subtype of SCLC tumors as well as the pulmonary neuroendocrine cells from which the SCLC tumors arise. 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 significantly reduces colony forming ability of TPCs in vitro and tumor initiating capacity in vivo. These data indicate that the expression of KSR2 is an essential driver of SCLC-A tumor propagating cell function, and therefore may play a role in SCLC tumor initiation. These findings shed light on a key distinct protein responsible for regulation in ASCL1 subtype SCLC tumors, and a potential subtype specific therapeutic target.