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Pancreatic Cancer Treatment Clues Uncovered From Genomic, Chromatin Profiles

NEW YORK – A subset of tumors from a rare, metastasis-prone subtype of pancreatic cancer known as adenosquamous carcinoma may be susceptible to treatments that target FGFR and other pathways identified through genomic and chromatin profiling, according to findings from investigators at the Mayo Clinic and elsewhere.

"Our results suggest that the genomic and epigenomic landscape of [adenosquamous carcinoma of the pancreas (ASCP) provide new strategies for targeting this aggressive subtype of pancreatic cancer," senior author Barrett Michael, a hematology and oncology researcher at the Mayo Clinic Arizona in Scottsdale, and his colleagues wrote in a paper published in Cancer Research.

Using a combination of DNA content flow cytometry, single-cell sequencing, exome sequencing, array-based comparative genomic hybdridization, and ATAC-seq, the team profiled somatic mutation, copy number, and chromatin accessibility patterns in 15 primary or metastatic ASCP tumor samples, including five patient-derived xenograft (PDXs) samples grown in mice.

Along with recurrent alterations affecting known driver genes such as TP53, KRAS, MYC, and CDKN2A — which also tend to be mutated in a more common form of pancreatic cancer called pancreatic ductal adenocarcinoma (PDAC) — the investigators saw chromatin regulatory changes and shifts in the composition of open chromatin that appeared to lend the tumors the ability to take on more stem cell-like qualities.

"Our study has shown that ASCPs have novel 'hits' (mutations and deletions) in genes that regulate tissue development and growth superimposed on the common mutational 'landscape' of a typical PDAC," Barrett said in a statement. "As a consequence, cells within the tumor have the ability to revert to a stem cell-like state that includes changes in cell types and appearance, and the activation of signaling pathways that drive the aggressive nature of ASCP."

To further explore the consequences of the chromatin accessibility changes, he and his colleagues used ATAC-seq to compare chromatin accessibility in half a dozen PDX models representing either ASCP or PDAC.

With this approach, they saw chromatin regions that remained accessible in all three ASCP PDX tumor models, but not in the PDAC tumor models, including regions housing a lysine methyltransferase enzyme-coding gene called SMYD2, and RORC, a gene coding for a nuclear hormone receptor known for its role as a pancreatic cancer stem cell regulator.

The researchers' ATAC-seq comparison also highlighted one ASCP PDX tumor model with open chromatin across a region that contained a fusion between the FGFR1 gene and ERLIN2 on chromosome 8, prompting follow-up organoid experiments that explored the possibility of targeting such tumors with the pan-FGFR inhibitor infigratinib.

They found that infigratinib could curb the growth of a tumor organoid containing both the FGFR1-ERLIN2 fusion and related open chromatin profile, suggesting that at least a subset of ASCP tumors may response to targeted treatment.

"[I]n addition to an epigenome that may promote stem cell features, we report that a subset of ASCP has activated FGFR signaling that can be targeted with current inhibitors," the authors proposed. "Although currently limited in numbers, the availability of PDXs and organoids that recapitulate the genomic and epigenomic lesions found in patient samples provide initial preclinical models to interrogate therapeutic targets in this lethal chemoresistant cancer."