Recurrent WNT pathway alterations are frequent in relapsed small cell lung cancer

作者：Alex H. Wagner, Siddhartha Devarakonda, Zachary L. Skidmore, Kilannin Krysiak, Avinash Ramu, Lee Trani, Jason Kunisaki, Ashiq Masood, Saiama N. Waqar, Nicholas C. Spies, Daniel Morgensztern, Jason Waligorski, Jennifer Ponce, Robert S. Fulton, Leonard B. Maggi, Jason D. Weber, Mark A. Watson, Christopher J. O’Conor, Jon H. Ritter, Rachelle R. Olsen, Haixia Cheng, Anandaroop Mukhopadhyay, İsmail Can, Melissa H. Cessna, Trudy G. Oliver, Elaine R. Mardis, Richard K. Wilson, Malachi Griffith, Obi L. Griffith, Ramaswamy Govindan · 发表于：Nature Communications · 年份：2018 · DOI：10.1038/s41467-018-06162-9 · 被引用次数：170 · 研究领域：Lung Cancer Research Studies、Peptidase Inhibition and Analysis、Neuroendocrine Tumor Research Advances

Nearly all patients with small cell lung cancer (SCLC) eventually relapse with chemoresistant disease. The molecular mechanisms driving chemoresistance in SCLC remain un-characterized. Here, we describe whole-exome sequencing of paired SCLC tumor samples procured at diagnosis and relapse from 12 patients, and unpaired relapse samples from 18 additional patients. Multiple somatic copy number alterations, including gains in ABCC1 and deletions in MYCL, MSH2, and MSH6, are identifiable in relapsed samples. Relapse samples also exhibit recurrent mutations and loss of heterozygosity in regulators of WNT signaling, including CHD8 and APC. Analysis of RNA-sequencing data shows enrichment for an ASCL1-low expression subtype and WNT activation in relapse samples. Activation of WNT signaling in chemosensitive human SCLC cell lines through APC knockdown induces chemoresistance. Additionally, in vitro-derived chemoresistant cell lines demonstrate increased WNT activity. Overall, our results suggest WNT signaling activation as a mechanism of chemoresistance in relapsed SCLC.