Single-cell analyses have shown that individual cancer cells can acquire mutations that make them more aggressive and resistant to chemotherapy. Thus, in some cases, even if chemotherapy seems to have been effective, a particularly aggressive cancer cell may survive and then cause a relapse in the future. The specific mutations that drive cancer progression and the mechanisms by which they do so are not well understood, delaying improvements in treating chemotherapy-resistant relapse.

Researchers from Harvard Medical School and Massachusetts General Hospital (both in Boston, MA) led by David Langenau decided to try a new approach to identify the relapse-driving cells in T-cell acute lymphoblastic leukemia (T-ALL), called leukemia-propagating cells (LPCs), using zebrafish. They induced T-ALL in transgenic zebrafish, then isolated individual leukemia cells and transplanted them into other zebrafish repeatedly to evaluate differences among the cells in the number of LPCs they eventually produced. A minority of leukemia cells produced significantly more LPCs after repeated transplant. Upon closer examination of these cells, the researchers found that a substantial subset of them had acquired a mutation that activated the Akt pathway. Activation of the Akt pathway increased the number of LPCs produced, increased the rate of cell growth and conferred resistance to dexamethasone chemotherapy (Cancer Cell 25, 336–378; 2014).

“The Akt pathway appears to be a major driver of treatment resistance [and also] increases overall growth of leukemic cells and increases the fraction of cells capable of driving relapse,” Langenau said in a press release.

Having elucidated a mechanism underlying relapse and chemotherapy resistance in T-ALL, Langenau's group next sought to apply this knowledge to improve treatment. They transplanted either primary Akt-negative leukemia cells or Akt-activated leukemia cells into zebrafish and then treated them with dexamethasone with or without an Akt inhibitor called MK2206. Dexamethasone alone was effective against Akt-negative leukemia but not against Akt-activated leukemia, as predicted. But the addition of MK2206 restored dexamethasone sensitivity in Akt-activated leukemia, resulting in remission.

The work has implications for the treatment of T-ALL in humans. It is likely that Akt-activated cells resistant to dexamethasone are already present in some patients, even those who have not been exposed to chemotherapy. And in patients undergoing chemotherapy, the selective pressure on leukemia cells to activate the Akt pathway is probably very strong. These patients may benefit from combination treatment with dexamethasone and Akt inhibitors such as MK2206. Langenau's team suggests that preclinical testing of such combination therapy is warranted.