The chromosome 18q21 deletion in nearly one third of pancreatic adenocarcinomas eliminates not only the tumor suppressor SMAD4, but also neighboring genes with important cellular roles, such as ME2. This is tolerated by cancer cells only because ME2 has a functionally redundant paralog, ME3, elsewhere in the genome. A study shows that these cells are vulnerable to ME3 silencing; this concept of collateral lethality could provide a new therapeutic strategy for a difficult-to-treat disease.

In nearly one third of pancreatic adenocarcinomas (PDAC), chromosome 18q21 is deleted, eliminating not only the tumor suppressor SMAD4, but also neighboring genes with important cellular roles, such as ME2. This is tolerated by cancer cells only because ME2 has a functionally redundant paralog, ME3, elsewhere in the genome. As such, according to a recent study, targeting ME3 in PDAC may represent a new therapeutic opportunity (Nature 2017;542:119–23).

“A few years ago, we coined the phrase ‘collateral lethality’ to describe how the co-deletion of passenger genes alongside tumor suppressors can confer vulnerabilities specific to cancer cells,” says senior author Ronald DePinho, MD, president of The University of Texas MD Anderson Cancer Center in Houston. “Our proof-of-concept was ENO1, a key glycolytic gene that's lost as part of the 1p36 deletion in glioblastoma—the cells did just fine until we silenced ENO2 [Nature 2012;488:337–42]. This current work in pancreatic cancer is our second example of collateral lethality.”

The malic enzymes ME2 and ME3 reside in the mitochondria, where they help keep reactive oxygen species (ROS) levels in check. Examining four PDAC cell lines, all lacking SMAD4 and, consequently, ME2, DePinho and his team observed a compensatory increase in ME3 expression. Knockdown of the latter significantly reduced cell proliferation and increased apoptosis; in transplanted PDAC-bearing mice, it also suppressed tumor growth and improved survival.

Mechanistically, in PDAC cells lacking both mitochondrial malic enzymes, “we showed that NADPH production is diminished, ROS levels rise, and this stress signal then activates AMPK,” says first author Prasenjit Dey, PhD. AMPK then prevents another protein, SREBP1, from upregulating BCAT2, which is normally involved in regenerating glutamate—an amino acid critical for the cells' survival, Dey adds.

“Glutamate-derived amino acids are necessary for new nucleotide synthesis,” DePinho explains. “Our study revealed a very important function for malic enzymes in sustaining the replicative potential of cancer cells.”

Nabeel Bardeesy, PhD, of Massachusetts General Hospital Cancer Center in Boston, notes that SMAD4's absence marks a particularly metastatic subset of PDAC. However, there are no established therapies targeting this loss. The latest findings from DePinho's group “help crystallize collateral lethality as a way to identify treatment strategies based not on a deleted tumor suppressor's function, but that of its neighbors on the same chromosome,” Bardeesy says. “I think this compelling concept will be explored in many more studies.”

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How collateral lethality works: In tumor cells lacking SMAD4 and ME2, suppressing ME3 reduces production of NADPH from malate, leading to unchecked ROS levels and, ultimately, cell death.

Designing a highly specific ME3 inhibitor would be ideal, DePinho says, but he acknowledges that structural similarities within the active sites of all malic enzymes make this challenging. “To avoid inadvertently inhibiting family members in normal cells, we'll want to look for other regions of ME3 that may be easier to target,” he says. “With delivery technology continuing to improve, RNAi-based strategies to silence ME3 could also be clinically feasible.” A third, broader approach involves going after additional components of this malic enzyme–regulated metabolic pathway that PDAC cells depend on to survive.

DePinho points out that the SMAD4 locus is also eliminated in approximately 14% of head and neck squamous cell carcinomas, and in up to 10% of gastric and esophageal cancers. “Basically, there are multiple ME2-deficient cancers for which collateral lethality may present a new therapeutic avenue,” he says. –Alissa Poh

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©2017 American Association for Cancer Research.
2017
American Association for Cancer Research.