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Researchers Identify New Treatment Target for Esophageal Cancer

NEW YORK (GenomeWeb) – Scientists at the Institute of Cancer Research in London have identified a novel treatment target in esophageal cancer that could be affected using an existing drug.

Their study, published earlier this week in Gut, discovered a genetic weakness in esophageal cancer cells that causes them to be extremely sensitive to the BTK/ERBB2 kinase inhibitor ibrutinib (AbbVie's Imbruvica), which doctors already use to treat B-cell cancers such as mantle cell lymphoma and chronic lymphocytic leukemia.

The team demonstrated that esophageal cancer cells with a cancer-causing mutation in the MYC gene become reliant on a second gene called BTK.

"The DNA of cancer cells tends to be extremely mutated — whilst these mutations cause cancer, they also often make cells addicted to genes normal cells are not," senior author and Institute of Cancer Research professor Christopher Lord said in a statement.

By blocking the function of BTK using ibrutinib in cancer cell lines, the researchers were able to kill the esophageal cancer cells while leaving normal cells relatively untouched.

Esophageal carcinoma has been classified into two main subtypes: esophageal adenocarcinoma (EAC) and esophageal squamous cell carcinoma (ESCC). The researchers noted that current treatment options for patients with esophageal cancers are extremely limited. Platinum-based chemotherapy remains the mainstay of treatment for EAC. However, although a small number of targeted therapeutic approaches exist for patients with EAC, there are no licensed targeted therapies for patient with ESCC, the authors noted.  

Previous work to define the disease's mutational make up have highlighted the presence of recurrent mutations, including amplifications of oncogenes such as CCND1, ERBB2, and MYC.

For their new study, the researchers compiled copy number and mutation profiles of 17 esophageal tumor-derived cell lines using array comparative genomic hybridization and exome sequencing data, and classified the cell lines according to the presence or absence of variations in specific oncogenes. The found mutations that were consistent with the mutational spectrum of the disease in the clinic, including mutations in genes such as TP53, SYNE1, CDKN2A, ERBB2, CCND1, and MYC.

The researchers then assessed the sensitivity of each cell line to an in-house library of 80 drugs that are currently used for the treatment of cancer or which are in late-stage development, and further assessed whether drug sensitivity differed according to whether the cell lines were derived from EAC or ESCC. They also looked at recent RNA interference screen data of sensitivity for the same tumor cell lines and an additional 103 tumor cell lines to short interfering RNAs designed to target a panel of 714 genes encoding kinases and kinase-related proteins, as a means to identify candidate genetic dependencies in esophageal cancers.

"As kinases represent a pharmacologically tractable family of enzymes, we reasoned that doing so might also identify targetable vulnerabilities associated with molecularly defined subsets of the disease," the authors wrote.

When integrated, the data from these analyses suggested the presence of several dependencies within the esophageal cancer cell lines, with one of the "most profound associations" being between MYC amplification and sensitivity to BTK siRNA, the team said.

Lord and his colleagues identified a series of candidate targets in esophageal cancer, including a sensitivity to inhibition of the kinase BTK in MYC amplified esophageal tumor cell lines. They realized that MYC's dependency on the BTK kinase could be elicited with ibrutinib.

"In both MYC and ERBB2 amplified tumor cells, ibrutinib downregulated ERK-mediated signal transduction, cMYC Ser-62 phosphorylation, and levels of MYC protein, and elicited G1 cell cycle arrest and apoptosis, suggesting that this drug could be used to treat biomarker-selected groups of patients with esophageal cancer," the authors wrote.

Based on their results, Lord and his team have begun a proof-of-concept single-arm Phase II trial of ibrutinib in patients with advanced esophagogastric cancer harboring MYC or ERBB2 amplifications.

They also noted the limitations of using cancer cell lines, and recommended that future studies be conducted with patient-derived tumor organoids and xenografts. These platforms will be especially important in order for researchers to determine possible mechanisms of resistance to BTK inhibition that might emerge as a results of treatment.