Late Diagnosis of Isolated Agenesis of Cranial Nerve VIII

Abstract

Despite significant advancement in developing selective FLT3 inhibitors, resistance to treatment is common even on continued therapy. Acquisition of on-target mutations or adaptation to MAPK, JAK2, and ABL signaling pathways drive treatment failure and disease relapse. While combinatorial targeting of all escape routes in pre-clinical models demonstrated its efficacy, its clinical application is challenging due to drug-drug interaction and differing pharmacokinetics of the inhibitors. We reasoned that selective polypharmacology targeting could lead to a durable response with reduced toxicity. A cell-based screening was carried out to identify inhibitors targeting FLT3, RAS-MAPK, BCR-ABL, and JAK2 to target the adaptive resistance observed with FLT3 inhibitors. Here we show that pluripotin is an equipotent inhibitor of FLT3, BCR-ABL, and JAK2, in addition to inhibiting Ras-GAP and ERK1. Structural modeling studies revealed that pluripotin is a type-II kinase inhibitor that selectively binds with inactive conformations of FLT3, ABL, and JAK2. Pluripotin showed potent inhibitory activity on both mouse and human cells expressing FLT3ITD, including clinically challenging resistant mutations of the gatekeeper residue, F691L. Likewise, pluripotin suppressed the adaptive resistance conferred by the activation of RAS-MAPK pathways, BCR-ABL, and JAK2 signaling. Pluripotin treatment curbed the progression of AML in multiple in vivo models including patient-derived primary AML cells in mouse xenotransplants. As a proof of concept, we demonstrate that targeted polypharmacological inhibition of key signaling nodes driving adaptive resistance can provide a durable response.