PB1648 THE CLINICAL RELEVANCE OF INDIRECT MYC INHIBITORS FOR PERSONALIZED T‐ALL TREATMENT
Authors: H. Ahlert, S. Bhatia, M. Sönnichsen, N. Dienstbier, M. Remke, U. Fischer, J. Hauer, A. Borkhardt
Journal: HemaSphere (2019)

Background: Therapy refractory and relapsed T cell lymphoblastic leukemia (T‐ALL) is still one of the most common reasons for cancer related death in children. The current therapy option is stem cell transplantation, which is associated with many complications and therefore, targeted therapies with low toxicity profiles are urgently needed. The oncogenic transcription factor MYC is excellently suited as a therapeutic target as it has proven to be a potent driver for T‐ALL development. So far, direct inhibition of MYC is not possible due to its undruggable structure. Hence, inhibition of MYC can be achieved indirectly or by targeting synergistic pathways. Aims: The aim of our study is to identify major key regulators in MYC driven T‐ALL. Targeting synergistic pathways of MYC like the PI3K/AKT signalling pathway seems to be a promising strategy to precisely eliminate tumour cells without affecting healthy cells. Methods: We profiled several T‐ALL and a T cell lymphoma cell line model with a specific interest for genes implicated in MYC regulation on mRNA and protein level including major MYC regulator pathways like Notch‐signaling, Raf‐MEK‐ERK cascade, BRD4, protein folding and PI3K/AKT/mTOR pathway. In parallel, we designed a leukemia specific compound library (n = 180) of diverse phase I ‐ III inhibitors including clinically available chemotherapeutics, diverse kinase‐, HSP90‐, proteasome‐, HDAC‐ and BET inhibitors. Synergy studies were performed with preselected compounds in an 11 × 11 matrix. Results: Protein and mRNA profiling displayed a varying distribution of MYC expression, including its associated downstream and upstream signaling pathways. PTEN loss of function mutants (PTEN mut) are described to have an increased pAKT level due to PI3K dysregulation which has a stabilising effect on MYC, and besides that it has also been associated with a poor outcome in T‐ALL patients. Interestingly, PTEN mut expressing T‐ALL cell lines (MOLT4, HPBALL, JURKAT and SUPT1) shown a simultaneous hyper AKT phosphorylation (pAKT), whereas, PTEN wildtype (wt) cell lines (TALL1, HSB2, DND41 and PEER) exhibit remarkably low pAKT. However MYC expression did not strongly correlate with the PTEN/pAKT status. Therefore, we stratified high and low MYC expressing cell lines according to their PTEN mutational status. Thus, we screened the T‐ALL cell lines on our compound library, which covered major MYC regulatory pathways. Remarkably, specific classes of drugs, including PI3K/AKT/mTOR and Aurora kinase A inhibitors exhibited a promising drug profile in PTEN mut models, while MEK and ERK1/2 inhibitors were particularly potent in PTEN wt. These results were corroborated in a (PTEN wt) low MYC expressing T‐ALL1 cell line model, which showed an increased sensitivity toward Aurora Kinase A inhibitors when MYC was overexpressed. Furthermore, combination studies of PI3K inhibitors with the established indirect MYC inhibitors, e.g. BRD4 or Aurora kinase A inhibitors revealed an synergistic effect in PTEN mut when compared to PTEN wt expressing cell lines. Summary/Conclusion: The source of MYC overexpression is very heterogeneous because its maintenance is highly dependent upon many regulatory pathways. Knocking down the oncogenic transcription factor MYC via synergistic pathways is a promising strategy for targeted therapies in the future.