Pediatric patients that relapse with T-cell acute lymphoblastic leukemia often don’t respond to the standard treatment. A new publication in the notable journal Nature Communications documents how Prof. Connie Jimenez and Dr. Jules Meijerink tackle the daunting task of finding kinase inhibitors that may provide new treatment options for these patients.

One in five pediatric patients with T-cell acute lymphoblastic leukemia (T-ALL) will relapse within four years. Often patients who relapse also develop resistance to high-dose chemotherapy treatment. Therefore, additional treatments are urgently needed. In other cancers, many patients benefit from treatments that inhibit kinases. Kinases are proteins that “switch on” other proteins in a process known as phosphorylation. They play a vital role in cell communication relating to growth and differentiation, among other biological processes. Inhibiting protein kinases can be a useful tool for controlling cancer. However, until now, identifying the key kinase players in T-ALL has proved challenging.

Searching for the needle in a haystack
With over 500 protein kinases in humans, identifying the key kinase players in T-ALL is like looking for a needle in a haystack. The search often begins by looking for genomic abnormalities which specifically activate a kinase (or kinases), which could indicate an involvement in cancer proliferation. Unfortunately, kinases activated by genomic abnormalities are rare in T-ALL, and so the challenge remains to find unusually active kinases associated with this disease.

To elicit information on kinase pathway activation and signaling networks in T-ALL, Valentina Cordo, Prof. Connie Jimenez, Dr. Jules Meijerink and their teams based at Cancer Center Amsterdam and the Princess Maxima Center in Utrecht used phosphoproteomics. Phosphoproteomics, the study of phosphorylated proteins, can indicate which proteins or pathways are “switched on” by phosphorylation. The team did this by using high-throughput mass spectrometry to produce a highly complex dataset. They then analyzed the data in conjunction with a dedicated bioinformatic database which allows users to reduce complex mass spectrometry phosphoproteomics data into a simple ranking of kinase activity. “We ranked the kinases from the most active to the least active in 11 different T-ALL cell lines,” explains Prof. Jimenez.

Verifying the findings
“Our results confirmed the activation of known kinases in T-ALL, namely LCK, SRC, CDKs, but also uncovered the activation of the INSR/IGF-1R axis. This activation happened in the absence of any activating mutations in the INSR or IGF1R gene,” says Dr. Jules Meijerink, who is the joint team leader along with Prof. Jimenez.

Based on the kinase activation patterns in T-ALL, the team then tested the efficacy of inhibitors on the most active kinases in 11 leukemia cells lines. “We found that simultaneous inhibition of LCK/SRC and INSR/IGF-1R is highly effective and synergistic, indicating a novel possible treatment combination,” reveals Dr. Meijerink. The team then confirmed their findings in cells obtained from four different patient-derived mouse models. “Our analysis of active proteins reveals a more complete picture of leukemia and will allow us to design a personalized treatment strategy,” says Dr. Meijerink.

Found: Potential kinase inhibitors for T-ALL
This study demonstrates that phosphoproteomic profiling can discover novel targets for T-ALL therapies. “Future patients could receive individualized treatment based on the kinase activation profile of their leukemia,” explains Prof. Jimenez.

Read the full article here:

For more information contact: Prof. Connie R. Jimenez or Dr. Jules P.P. Meijerink

Text by Lynita Howie.

Valentina Cordo (Princess Maxima Center and Amsterdam UMC), Mariska Meijer (Princess Maxima Center), Rico Hagelaar (Princess Maxima Center), Richard de Goeij-de Haas (Amsterdam UMC), Vera Poort (Princess Maxima Center), Alex Henneman (Amsterdam UMC), Sander Piersma (Amsterdam UMC), Thang Pham (Amsterdam UMC), Koichi Oshima (Columbia University Medical Center), Adolfo Ferrando (Columbia University Medical Center), Guido Zaman (Oncolines B.V.), Connie Jimenez (Amsterdam UMC) and Jules Meijerink (Princess Maxima Center).

This study was supported by the Dutch Cancer Society - KWF Kankerbestrijding (grant KWF2016_10355 to Dr. J. Meijerink-Princess Maxima Center and Prof. C. Jimenez – Amsterdam UMC).

Cancer Center Amsterdam and the Netherlands Organization for Scientific Research (NWO) provided the mass spectrometry infrastructure.