Genomic and epigenomic landscaping defines new therapeutic targets for adenosquamous carcinoma of the pancreas

Elizabeth Lenkiewicz, Smriti Malasi, Tara L. Hogenson, Luis F. Flores, Whitney Barham, William J. Phillips, Alexander S. Roesler, Kendall R. Chambers, Nirakar Rajbhandari, Akimasa Hayashi, Corina E. Antal, Michael Downes, Paul M. Grandgenett, Michael A. Hollingsworth, Derek Cridebring, Yuning Xiong, Jeong Heon Lee, Zhenqing Ye, Huihuang Yan, Matthew C. HernandezJennifer L. Leiting, Ronald M. Evans, Tamas Ordog, Mark J. Truty, Mitesh J. Borad, Tannishtha Reya, Daniel D. von Hoff, Martin E. Fernandez-Zapico, Michael T. Barrett

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

Abstract

Adenosquamous cancer of the pancreas (ASCP) is a subtype of pancreatic cancer that has a worse prognosis and greater metastatic potential than the more common pancreatic ductal adenocarcinoma (PDAC) subtype. To distinguish the genomic landscape of ASCP and identify actionable targets for this lethal cancer, we applied DNA content flow cytometry to a series of 15 tumor samples including five patient-derived xenografts (PDX). We interrogated purified sorted tumor fractions from these samples with whole-genome copy-number variant (CNV), whole-exome sequencing, and Assay for Transposase-Accessible Chromatin using sequencing (ATAC-seq) analyses. These identified a variety of somatic genomic lesions targeting chromatin regulators in ASCP genomes that were superimposed on well-characterized genomic lesions including mutations in TP53 (87%) and KRAS (73%), amplification of MYC (47%), and homozygous deletion of CDKN2A (40%) that are common in PDACs. Furthermore, a comparison of ATAC-seq profiles of three ASCP and three PDAC genomes using flow-sorted PDX models identified genes with accessible chromatin unique to the ASCP genomes, including the lysine methyltransferase SMYD2 and the pancreatic cancer stem cell regulator RORC in all three ASCPs, and a FGFR1-ERLIN2 fusion associated with focal CNVs in both genes in a single ASCP. Finally, we demonstrate significant activity of a pan FGFR inhibitor against organoids derived from the FGFR1-ERLIN2 fusion-positive ASCP PDX model. Our results suggest that the genomic and epigenomic landscape of ASCP provide new strategies for targeting this aggressive subtype of pancreatic cancer.

Original languageEnglish (US)
Pages (from-to)4324-4334
Number of pages11
JournalCancer research
Volume80
Issue number20
DOIs
StatePublished - Oct 15 2020

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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