with autophagosomes (green),
a process that happens during
mitophagy in cancer cells
treated with FLT3 inhibitor
Image from Besim Ogretmen
and Mohammed Dany/MUSC
Research published in Blood has revealed a mechanism that confers treatment resistance in FLT3-mutated acute myeloid leukemia (AML), as well as a drug that might overcome that resistance.
Researchers found that ceramide-dependent mitophagy plays a key role in drug-mediated AML cell death.
“Ceramide, a pro-cell-death lipid, kills cancer cells by causing them to eat their own mitochondria,” explained study author Besim Ogretmen, PhD, of the Medical University of South Carolina (MUSC) Hollings Cancer Center in Charleston, South Carolina.
AML cells with FLT3-ITD inhibit ceramide synthesis and thereby become resistant to cell death. FLT3 inhibitors have been developed to combat this resistance, but they’ve fallen short of expectations.
“Unfortunately, regardless of the inhibitor, the problem of resistance to FLT3-targeted therapy has persisted,” said study author Mohammed Dany, an MD/PhD student at MUSC.
However, Dany, Dr Ogretmen, and their colleagues were able to overcome this resistance with a synthetic ceramide analogue known as LCL-461.
In vitro, the drug reactivated mitophagy and killed AML cells that were resistant to treatment with the FLT3 inhibitor crenolanib.
In mice with crenolanib-resistant human AML xenografts, LCL-461 eliminated AML cells from the bone marrow.
A positively charged molecule, LCL-461 is attracted to the mitochondria of cancer cells, which become negatively charged through the Warburg effect. The researchers said this limits off-target effects that can occur with less specific inhibitors of FLT3 signaling.
Furthermore, Dr Ogretmen’s lab has tested the safety of LCL-461 in previous studies and reported that it had no major side effects at therapeutically active doses.
Dr Ogretmen and his colleagues’ next step is to perform large animal studies with LCL-461.
“We are very excited about this,” Dr Ogretmen said. “Head and neck cancers also respond to this drug very well. What we are trying to do is really cure cancer one disease at a time, and we are digging and digging to understand the mechanisms of how these cancer cells escape therapeutic interventions so that we can find mechanism-based therapeutics to have more tools for treatment.”
LCL-461 was developed at MUSC. The MUSC Foundation for Research Development has patented the drug and licensed it to Charleston-based startup SphingoGene, Inc.
