Journal Article

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

Trani, Lee, Watson, Mark A., Mardis, Elaine R., Krysiak, Kilannin, Waqar, Saiama N., Waligorski, Jason, Olsen, Rachelle R., Spies, Nicholas C., Maggi, Leonard B., Morgensztern, Daniel, Can, Ismail, Govindan, Ramaswamy, Weber, Jason D., Oliver, Trudy G., Wagner, Alex H., Kunisaki, Jason, O’Conor, Christopher J., Ramu, Avinash, Ritter, Jon H., Masood, Ashiq, Griffith, Obi L., Cheng, Haixia, Wilson, Richard K., Devarakonda, Siddhartha, Griffith, Malachi, Ponce, Jennifer, Skidmore, Zachary L., Mukhopadhyay, Anandaroop, Fulton, Robert S., Cessna, Melissa H.

2018

Overview

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. Small cell lung cancer (SCLC) patients frequently relapse and become resistant to chemotherapy. Here, the authors analyse the genomic and transcriptomic landscape of primary and relapsed SCLC patients as well as in vitro models, and discover that activation of WNT signalling can drive chemotherapy resistance.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 45/23 / 45/91 / 692/308/2056 / 692/4028/67/1612/2143 / Activation / Adenomatous polyposis coli / Adenomatous Polyposis Coli Protein - genetics / ASCL1 protein / Basic Helix-Loop-Helix Transcription Factors - genetics / Biotechnology / Cadherins - genetics / Cell Line, Tumor / Chemoresistance / Copy number / Data processing / Drug Resistance, Neoplasm - drug effects / Drug Resistance, Neoplasm - genetics / Exome Sequencing / Gene expression / Gene Expression Regulation, Neoplastic / Gene Knockdown Techniques / Gene sequencing / Heparan sulfate / Heterozygosity / Humanities and Social Sciences / Humans / Loss of Heterozygosity / Lung cancer / Lung Neoplasms - drug therapy / Lung Neoplasms - genetics / Lung Neoplasms - pathology / Molecular modelling / MSH2 protein / MSH6 protein / multidisciplinary / Mutation / Neoplasm Recurrence, Local / Regulators / Ribonucleic acid / RNA / Science / Science (multidisciplinary) / Signaling / Small cell lung carcinoma / Small Cell Lung Carcinoma - drug therapy / Small Cell Lung Carcinoma - genetics / Small Cell Lung Carcinoma - pathology / Wnt protein / Wnt Signaling Pathway - drug effects / Wnt Signaling Pathway - genetics