‘Collateral Lethality’ May Offer New Therapeutic Approach to Cancers of the Pancreas, Stomach, and Colon

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Prasenjit Dey, PhD

Prasenjit Dey, PhD

Cancer cells often delete genes that normally suppress tumor formation. These deletions also may extend to neighboring genes, an event known as “collateral lethality,” which may create new options for the development of therapies for several cancers. Scientists at The University of Texas MD Anderson Cancer Center have discovered that during early cancer development, when a common tumor suppressor known as SMAD4 is deleted, a nearby metabolic enzyme gene called malic enzyme 2 (ME2) also is eradicated, suggesting the possibility of malic enzyme inhibitors as a novel therapy approach. These study findings were published by Prasenjit Dey, PhD, a postdoctoral fellow in cancer biology at MD Anderson, and colleagues in Nature.1

“In an effort to expand therapeutic strategies beyond oncogenic targets to those not directly linked to cancer development, we have identified collateral lethal vulnerability in pancreatic cancers that can be targeted pharmacologically in certain patient populations,” said Dr. Dey. “Genomic data across several cancers further suggest this therapeutic strategy may aid many cancer patients, including those with stomach and colon cancers.”

Collateral Lethality and ME2 Levels

Collateral lethality occurs when tumor-suppressor genes are deleted, a nearly universal occurrence in cancer. Correspondingly, a large number of genes with no direct role in tumor progression also are deleted as a result of their proximity to tumor-suppressor genes.

We propose that highly specific ME3 inhibitors could provide an effective therapy for many cancer patients, but more research must be done.
— Ronald ­DePinho, MD

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SMAD4 is deleted in one-third of pancreatic cancers. The research team found that when the SMAD4 gene is eradicated in mice, it also results in depletion of ME2 levels. The genetic depletion of ME3, a sister gene to ME2, sets off a complex chain of events ultimately regulating the branched chain amino acid, which are crucial to tumor’s ability to thrive. Thus, if a therapy that inhibits ME3 could be developed, it might prevent ME2-deleted tumor growth.

“Our work suggests a mechanism for cell lethality involving the regulation of branched chain amino acids as crucial elements in pancreatic cancer by regulating ME3,” said ­Ronald ­DePinho, MD, Professor of Cancer Biology, senior author of the Nature paper, and President of MD Anderson. “We propose that highly specific ME3 inhibitors could provide an effective therapy for many cancer patients, but more research must be done.” ■

Disclosure: For full disclosures of the study authors, visit http://www.nature.com/nature/index.html.


1. Dey P, Baddour J, Muller F, et al: Genomic deletion of malic enzyme 2 confers collateral lethality in pancreatic cancer. Nature. January 18, 2017 (early release online).




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