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

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

Nature Communications, 2018, vol. 9, issue 1, 1-11

Abstract: Abstract 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.

Date: 2018
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DOI: 10.1038/s41467-018-06162-9

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