Interrogating the therapeutic impact of MYB overdose brought on by AKT inhibitor treatment in blood cancers.

Normal cells exhibit cell-type-specific molecular dependencies driven by lineage-associated genes. Notably, these dependencies remain functional following malignant transformation. One example of this phenomenon is seen in melanoma where cancer cells remain dependent on the lineage-defining transcription factor MITF (PMID:16510564). Importantly, oncogenic BRAF mutations (which occurs in approximately one half of melanoma cases) render MITF function sensitive to BRAF activity levels (PMID:18628967), thus creating a cancer-specific liability where inhibition of BRAF selectively kills melanoma cells through suppression of MITF function. Paradoxically, MITF overexpression can also have growth-inhibitory effects in BRAF-transformed melanocytes, suggesting that, akin to the toxic effects of oncogene overdose (PMID:26688666), excessive MITF signalling outputs can be detrimental to cancer cells.
In hematopoietic and lymphoid tissues, c-Myb is a lineage defining transcription factor whose function is necessary for cell survival. Not surprisingly, cancer cell lines of hematopoietic and lymphoid lineages are sensitive to c-Myb depletion (PMID:28753431). Therefore, c-Myb targeting could represent a lineage-addiction-based therapeutic strategy in heme malignancies. One obvious limitation to such an approach is the inherent dependence of normal hematopoietic tissue to the activity of c-Myb, and the potential toxicities that could be associated with systemic inhibition of c-Myb. However, we reasoned that if oncogenic signal transduction rewiring in heme cancers confers specific oncogenes with a neomorphic ability to regulate c-Myb function, it would render these oncogenes attractive therapeutic targets for these diseases.
The PI3K pathway is one of the most commonly deregulated pathways in human cancer. PI3Ks are heterodimeric lipid kinases that drive the generation of phosphoinositide second messengers that activate a number of effector proteins including AKT (PMID:12094235) . Activation of the PI3K pathway in human leukemias and lymphomas is well documented (PMID:25100567,32326335) and has prompted a number of clinical trials to investigate the activity of PI3K pathway inhibitors. Interestingly, AKT inhibitors have not been assessed very extensively in hematological cancers (PMID: 34858045). Our preliminary data, and that of others (PMID:26989080) show that AKT inhibitors can induce significant cytotoxic responses in leukemic cell lines (Figure 1). Interestingly, we find that these effects correlate with an upregulation of c- MYB protein (Figure 2A). Similar effects are seen following treatment with an inhibitor of PI3K6, the major source of PI3K activity in hematopoietic cells, but not when treated with the MEK inhibitor trametinib (Figure 2B). Altogether, these data suggest a potential link between AKT activation and c-Myb regulation in hematological malignancies. Consistently, it has been previously shown that knockdown of FOXO1, a transcription factor that is negatively regulated by AKT phosphorylation, causes significant downregulation of MYB protein and MYB transcription targets (PMID:31557894). The same study showed that ectopic overexpression of c- Myb had a transient growth inhibitory effect in a lymphoma cell line. We therefore hypothesise that the molecular rewiring caused by PI3K pathway activation in blood cancers renders c-Myb subject to regulatory control by AKT through mechanisms this proposal will investigate (Figure 3).