Study Explains Anemia as Side Effect of Cancer Treatments

Research may improve the design of pharmaceuticals for leukemia and other types of cancer.

Many types of leukemia are characterized by a deficiency in the Pten enzyme, which normally keeps cell growth in check, or conversely, the over-activation of the enzyme Shp2 which enhances cell proliferation.

Some leukemia treatments work by inhibiting Shp2 and other enzymes involved in the same cellular systems. However, researchers at the University of California-San Diego School of Medicine have found that mice deficient in both enzymes cannot produce and sustain enough red blood cells.

The study also helps to explain why anemia is often a common side effect of anti-cancer therapies that target enzymes involved in tumor growth.

“Based on this unexpected finding, we might want to think about screening cancer patients’ genetic backgrounds for loss of Pten or Pten-regulated signals before prescribing anti-cancer drugs that might do more harm than good,” said senior author Gen-Sheng Feng, PhD, professor of pathology at UC San Diego School of Medicine. “In addition, this information could help guide better design of pharmaceuticals for leukemia and other types of cancer in the era of precision medicine.”

Feng and his team of scientists genetically engineered mice to be deficient in either Pten, Shp2 or both. The scientists observed that the Pten-deficient mice had elevated white blood cell counts, consistent with those found in patients with leukemia.

The Shp2-deficient mice experienced the opposite effect, however, with lower white blood cell counts. Mice deficient in both enzymes had normal white blood cell counts.

Researchers were surprised to discover that despite the apparent reversal of leukemia in mice lacking both enzymes, these mice had shorter lifespans than did those mice that lacked just one of the enzymes. As it turns out, deficiency in both enzymes results in lethal anemia.

The researchers deduced that the observed anemia was due to 2 factors: red blood cells failed to develop properly formed bone marrow and red blood cells that did form didn’t last as long as they should. The lack of red blood cells causes the body’s organs and tissues to suffocate as they do not receive the amount of oxygen they need.

To confirm the genetic studies, the researchers treated Pten-deficient mice with a Shp2 inhibitor or trametinib, a drug that inhibits another enzyme in the same cellular system as Shp2. Trametinib treats pancreatic and other types of cancers and is known for frequently causing anemia in patients who receive the therapy.

Sure enough, Feng’s team observed that in mice treated with trametinib, the effects were similar to removing the Shp2 gene or chemical inhibition of Shp2 in that they were severely anemic.

“What we’ve learned is that even if we know a lot about how individual molecules function in a cell, designing effective therapeutics that target them will require a more comprehensive understanding of the cross-talk between molecules in a particular cell type, and in the context of disease,” Feng concluded.