Does EphA2 Enzyme Keep a Leash on KRAS-Driven Lung Tumorigenesis?

Does EphA2 Enzyme Keep a Leash on KRAS-Driven Lung Tumorigenesis?

November 5, 2015

The enzyme ephrin receptor A2 (EphA2) normally blocks KRAS mutation-driven lung adenocarcinoma tumorigenesis, but a new study shows that EphA2 deletion mutation allows aggressive tumor growth-providing “important therapeutic targets” for this deadly form of lung cancer.

The enzyme ephrin receptor A2 (EphA2) normally blocks KRAS mutation-driven lung adenocarcinoma tumorigenesis, but a new study shows that EphA2 deletion mutation allows aggressive tumor growth-providing “important therapeutic targets” for this deadly form of lung cancer.

Using shRNA-mediated screening of 4,700 candidate human genes with tumor suppression potential, the team subsequently identified 16 genes in animal models that inhibit or slow KRAS- or TP53-driven tumorigenesis. The loss of EphA2 enhanced KRASG12D-driven lung adenocarcinoma carcinogenesis, they found.1

“We identified several tumor suppressors, including EphA2, loss of which promotes adenocarcinoma in the context of KRASG12D mutation,” the coauthors reported.1EphA2 loss promotes cell proliferation by activating ERK MAP kinase signaling and hedgehog signaling pathways, leading to tumorigenesis.”

A KRAS mutation is associated with tumorigenesis in 300 days, in animal models, noted senior author Inder Verma, PhD, Professor of Genetics and the Salk Institute’s Irwin and Joan Jacobs Chair in Exemplary Life Science.

“But without EphA2, the KRAS mutation leads to tumors in half the time, 120 to 150 days,” Dr. Verma noted. “This molecule EphA2 is having a huge effect on restraining cancer growth when KRAS is mutated.”

Up to 20% of all cancers harbor KRAS mutations, and these aberrations are particularly common in lung and colon cancers. EphA2 gene mutations were found in 54 of 230 patients whose lung adenocarcinoma tumor genomes were sequenced in the Cancer Genome Atlas Project, the coauthors noted.

“Oddly, among human lung cancer patients with EPhA2 mutations, around 8% of patients actually have high EphA2 expression,” cautioned coauthor Yifeng Xia, PhD, also at the Salk Institute. “So, in some instances, EphA2 is not suppressing tumors and may be context-dependent. Therefore, we need to carefully evaluate the molecule’s function when designing new therapeutics.”

EphA2 activation suppresses both cell signaling and cell proliferation, the team noted.  “We believe that the enzyme might serve as a potential drug target in KRAS-dependent lung adenocarcinoma,” explained lead study author Narayana Yeddula, PhD, a Salk research associate. 

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