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KSR1 regulates small-cell lung carcinoma tumor initiation and therapy resistance.

Deepan ChatterjeeRobert A SvobodaDianna H HuismanHeidi M VieiraChaitra RaoJames A AskewKurt W FisherRobert E Lewis
Published in: bioRxiv : the preprint server for biology (2024)
Small-cell lung cancer (SCLC) is designated a recalcitrant cancer due to its five-year relative survival rate of less than 7%. First line SCLC treatment has not changed in the last 40 years. The NeuroD1 subtype of SCLC (SCLC-N) commonly harbors MYC amplifications and other hallmarks of aggressive behavior. Finding novel therapeutic options that effectively eliminate residual disease observed after initial response to therapy is essential to improving SCLC patient outcome. Tumor-initiating cells (TICs) are reported as the sanctuary population within the bulk tumor responsible for therapeutic resistance and relapse. In contrast to earlier studies in which ERK activation is reported to be inhibitory to growth and tumor development, we show that KSR1 signaling is conserved in SCLC-N and that it regulates tumor initiation through ERK. Thus, KSR1 function in SCLC-N serves as a novel model for understanding the role of KSR1-dependent signaling in normal and malignant tissues. We further show that KSR1 mediates cisplatin resistance in SCLC-N cells. CRISPR/Cas9-mediated KSR1 knockout causes a dramatic increase in sensitivity to cisplatin and is coincident with a marked decrease in TICs, indicating that targeting KSR1 might be selectively toxic to cells responsible for therapeutic resistance and tumor initiation. Our data show that KSR1, a molecular scaffold for the Raf/MEK/ERK signaling cascade, is critical for tumor initiation and clonogenicity, both in vitro and in vivo in the highly aggressive, metastatic and therapy resistant NeuroD1 subtype of SCLC. These findings shed light on a key distinct protein responsible for regulation in SCLC-N tumors, and a potential subtype specific therapeutic target.
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