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Advanced Gastric Cancer Multiomic Analysis Reveals New Potential Therapeutic Targets

NEW YORK – A research team from Japan has uncovered that gastric cancer metastases in the peritoneum show more changes in receptor tyrosine kinase (RTK) and mitogen-activated protein (MAP) kinase pathways than corresponding primary gastric cancers, which could be exploited for targeted treatment. In addition, the researchers discovered separate molecular subgroups that offer still other targeted treatment opportunities.

"Peritoneal metastasis, a hallmark of incurable gastric cancer, presently has no curative therapy and its molecular features have not been examined extensively," co-first and co-corresponding author Yosuke Tanaka, a cellular signaling researcher at the National Cancer Center Research Institute, and his colleagues wrote in a study published in Nature Cancer on Monday.

They noted that around half of the RTK or MAP kinase alterations identified in the peritoneal metastases appeared amenable to targeted treatment strategies. They also saw signs that targeting a transcriptional enhancer pathway that is altered in a molecular subgroup of the metastatic tumors might help stanch resistance to other therapies.

Using whole-genome sequencing, RNA sequencing, array-based methylation profiling, chromatin immunoprecipitation sequencing, immunohistochemistry, and other approaches, the researchers tallied somatic mutations, mutational signatures, copy number changes, expression shifts, gene fusions, and gene regulatory shifts in malignant ascitic fluid samples and cell lines developed from these samples for nearly 100 individuals with advanced gastric cancer. They then compared these features with those found in matched normal and primary tumor samples.

"In this study, we present the landscape of [gastric cancer] with peritoneal metastasis using the most comprehensive genomic/epigenomic analyses to date," the authors explained. "These observations updated our understanding of the biology of cancer cells and help identify molecular vulnerabilities in incurable advanced [gastric cancer]."

Along with an uptick in MAP kinase, RTK-Ras, or TP53 pathway alterations or amplifications in the peritoneal metastases, the team found two molecular subgroups within the peritoneal metastatic gastric cancer cell lines using expression profiles, gene set enrichment analysis, and regulatory clues.

In particular, the results pointed to the presence of metastatic tumors with pronounced super enhancer activity, particularly in and around loci containing the ELF3, KLF5, and EHF transcription factor-coding genes. Another molecular subgroup was marked by "epithelial mesenchymal transition" (EMT) features, CDKN2A/B gene loss, higher-than-usual SMAD3 super enhancer activity, and a related rise in TGF-beta pathway signaling, along with enhanced expression of the TEAD1 transcriptional effector.

When the researchers attempted to target the TGF-beta subtype using a TEAD inhibitor known as K-975 in a mouse model of the disease or in gastric cancer cell lines classified as EMT from the Cancer Cell Line Encyclopedia, they found that the treatment appeared to curb tumor growth as well as resistance to other types of gastric cancer treatment such as MEK1/2 inhibition.

From such initial results, the authors suggested that "combination therapy of TEAD inhibitors and other agents could be a promising approach to overcome the therapeutic resistance of [gastric cancer] with the EMT trait, which exhibits the worst prognosis in [gastric cancer]."

"[O]ur data greatly contribute to a better understanding of [gastric cancer] cells with peritoneal metastases," the authors concluded, "and provide the possibility of effective therapeutic strategies for this intractable condition with a mean overall survival of only [three to six] months."

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