Evaluation of the antineoplastic effects of the multikinase inhibitor AD80 in hematologic malignancies with constitutive activation of tyrosine-kinase pathways

Abstract

Activation of signaling pathways mediated by tyrosine kinases contributes to the development and progression of hematological malignancies, of which we can highlight myeloproliferative neoplasms (MPN) BCR::ABL1 (Ph+), JAK2V617F and CSF3RT618I positive, and acute myeloid leukemias (AML) FLT3-ITD positive. These mutations have in common the constitutive activation of downstream targets including the PI3K/AKT/mTOR, MAPK, and JAK2/STAT pathways. Despite the great success of tyrosine kinase inhibitors in the treatment of chronic myeloid leukemia (Ph+), the emergence of mutations such as BCR::ABL1T315I indicates the need to expand the antineoplastic arsenal even in this context. FLT3 inhibitors have also improved clinical outcomes in AML, but not as dramatically as seen in CML. On the other hand, JAK2 inhibitors improve the symptoms but do not change the natural history of Ph NPM negative. There is also chronic neutrophilic leukemia (CSF3RT618I) which has very limited therapeutic options. In this scenario, the search for new antineoplastic agents is of interest. AD80 is a multikinase inhibitor capable of inhibiting the activity of RET, RAF, S6K, ERK, and AKT. It is a new molecule and, therefore, few studies have been carried out to date verifying its effects on tumor cells. Current data indicate that AD80 is a potent molecule, showing high cytotoxicity and inhibiting proliferation and survival processes in in vitro and in vivo models. This research project aims to investigate the effects of AD80 in models of hematologic malignancies as constitutive activation of tyrosine kinase-mediated signaling pathways, analyzing both cellular and molecular aspects. Furthermore, the research project also aims to analyze the effects of AD80 under the protection conferred by the hematopoietic niche through co-culture models. (AU)