T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive type of leukemia in which too many T-cell lymphoblasts are found in the bone marrow and blood. Despite an overall survival of 80% in the pediatric setting, 20% of patients with T-ALL ultimately die from relapsed or refractory disease. Therefore, new ways of tackling the disease are urgently needed. Now, researchers from Princess Máxima Center for pediatric oncology in Utrecht, the Netherlands, collaborated with Amsterdam UMC and demonstrated in mice that blocking a protein chain reaction makes childhood leukemia cells more sensitive to an existing targeted treatment.

Their findings are published in the journal Nature Communications in a paper titled, “Phosphoproteomic profiling of T-cell acute lymphoblastic leukemia reveals targetable kinases and combination treatment strategies.”

“Protein kinase inhibitors are amongst the most successful cancer treatments, but targetable kinases activated by genomic abnormalities are rare in T-cell acute lymphoblastic leukemia,” wrote the researchers. Nevertheless, kinases can be activated in the absence of genetic defects. Thus, phosphoproteomics can provide information on pathway activation and signaling networks that offer opportunities for targeted therapy. Here, we describe a mass spectrometry-based global phosphoproteomic profiling of 11 T cell acute lymphoblastic leukemia cell lines to identify targetable kinases.”

“We’ve shown that looking at protein activity gives a more complete picture of the weaknesses in leukemia. In future, our research could help discover new treatment strategies for children with the disease who don’t respond to standard treatment,” explained Valentina Cordo, a PhD student in the Meijerink group at the Princess Máxima Center.

“Often, scientists tell cancer cells apart from healthy ones by looking at faults in the DNA. In our new study, we looked at proteins instead. We looked for proteins with unusually high activity, which likely point to ways for cancer cells to evade treatment. These could be potential targets for therapy.”

Analyzing all the protein switches in 11 different kinds of T-ALL cells, the team found a number of proteins already known to be linked to the disease, including two proteins called LCK and SRC. They also found an overactive chain reaction of proteins called INSR/IGF-1R.  “Excitingly, we found that blocking LCK or SRC at the same time as INSR/IGF-1R killed the cancer cells very effectively. Even at low concentrations of the drugs we used, the combination was more effective than either treatment on its own,” noted Cordo.

To further study the drug combination, the researchers looked at the effect in leukemia cells from children with T-ALL grown in mice. In those cells with high activity for both the SRC protein and the INSR/IGR-1R chain reaction, the drug combination was again very effective. Cordo added: “There were no faults in the genes that coded for these proteins, which shows us that protein activity is a valuable clue in looking for drug targets in ALL.”

Further studies are needed in the lab and in animal studies before clinical trials can begin, but these findings pave the way for improving treatment strategies for children with ALL who don’t respond to standard treatment.

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