Abstract
Mutations in receptor tyrosine kinases (RTKs) FLT3 and KIT are frequent and associated with poor outcomes in acute myeloid leukemia (AML). Although FLT3 inhibitors (FLT3i) are clinically effective, remissions are short-lived due to secondary resistance characterized by acquired mutations constitutively activating the RAS/MAPK pathway. Hereby, we report pre-clinical efficacy of co-targeting SHP2, a critical node in MAPK signaling, and BCL2 in RTK-driven AML. The allosteric SHP2 inhibitor RMC-4550 suppressed proliferation of AML cell lines with FLT3 and KIT mutations, including cell lines with acquired resistance to FLT3i. We demonstrate that SHP2 inhibition unveils an Achilles’ heel of AML, increasing apoptotic dependency on BCL2 via MAPK-dependent mechanisms, including upregulation of BMF and downregulation of MCL1. Consequently, RMC-4550 and venetoclax are synergistically lethal in FLT3- or KIT-mutant AML cell lines, and in clinically relevant xenograft models. Our results provide new mechanistic rationale and preclinical evidence for co-targeting SHP2 and BCL2 in RTK-driven AML.
Significance There is an unmet need for effective therapies targeting the MAPK pathway to overcome resistance in RTK-driven AML. We report that pharmacologic co-inhibition of SHP2 and BCL2 has synergistic anti-leukemia activity in preclinical models of AML with FLT3 and KIT mutations and holds potential clinical utility.
Competing Interest Statement
C. Stahlhut is a former employee and stockholder of Revolution Medicines, Inc. and a current employee and stockholder of BridgeBio Pharma, Inc. B. J. Lee is a current employee of Revolution Medicines Inc. J. A. Chukinas is a current employee of Outpace Bio. S. K. Tasian reports research funding unrelated to this work from Beam Therapeutics, Kura Oncology, Incyte Corporation, scientific advisory boards for Aleta Biotherapeutics, Kura Oncology, Syndax Pharmaceuticals, consulting for bluebird bio and travel support from Amgen. C. C. Smith reports research funding from Abbvie, Inc. and Revolution Medicines, and has served as an advisory board member of Abbvie, Inc. and Genentech.
