| Autor: |
Wagner, Alex H., Devarakonda, Siddhartha, Skidmore, Zachary L., Krysiak, Kilannin, Ramu, Avinash, Trani, Lee, Kunisaki, Jason, Masood, Ashiq, Waqar, Saiama N., Spies, Nicholas C., Morgensztern, Daniel, Waligorski, Jason, Ponce, Jennifer, Fulton, Robert S., Maggi, Leonard B., Weber, Jason D., Watson, Mark A., O’Conor, Christopher J., Ritter, Jon H., Olsen, Rachelle R. |
| Zdroj: |
Nature Communications; 9/17/2018, Vol. 9 Issue 1, p1-1, 1p |
| Abstrakt: |
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. [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
| Externí odkaz: |
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