Allosteric SHP2 inhibition increases apoptotic dependency on BCL2 and synergizes with venetoclax in FLT3- and KIT-mutant AML

Bogdan Popescu; Carlos Stahlhut; Theodore C Tarver; Sydney Wishner; Bianca J Lee; Cheryl A C Peretz; Cuyler Luck; Paul Phojanakong; Juan Antonio Camara Serrano; Henry Hongo; Jose M Rivera; Simayijiang Xirenayi; John A Chukinas; Veronica Steri; Sarah K Tasian; Elliot Stieglitz; Catherine C Smith

doi:10.1016/j.xcrm.2023.101290

Allosteric SHP2 inhibition increases apoptotic dependency on BCL2 and synergizes with venetoclax in FLT3- and KIT-mutant AML

Cell Rep Med. 2023 Nov 21;4(11):101290. doi: 10.1016/j.xcrm.2023.101290.

Authors

Bogdan Popescu¹, Carlos Stahlhut², Theodore C Tarver³, Sydney Wishner³, Bianca J Lee², Cheryl A C Peretz⁴, Cuyler Luck⁵, Paul Phojanakong⁶, Juan Antonio Camara Serrano⁶, Henry Hongo⁷, Jose M Rivera⁷, Simayijiang Xirenayi⁷, John A Chukinas⁸, Veronica Steri⁶, Sarah K Tasian⁹, Elliot Stieglitz⁴, Catherine C Smith¹⁰

Affiliations

¹ Division of Hematology/Oncology, Department of Medicine, University of California, San Francisco, San Francisco, CA, USA; Carol Davila University of Medicine and Pharmacy, Bucharest, Romania.
² Revolution Medicines, Inc., Redwood City, CA, USA.
³ Division of Hematology/Oncology, Department of Medicine, University of California, San Francisco, San Francisco, CA, USA.
⁴ Department of Pediatrics, Benioff Children's Hospital, University of California, San Francisco, San Francisco, CA, USA; Helen Diller Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA.
⁵ Department of Medicine, University of California, San Francisco, San Francisco, CA, USA.
⁶ Preclinical Therapeutics Core, Helen Diller Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA; Helen Diller Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA.
⁷ Helen Diller Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA.
⁸ Division of Oncology, Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
⁹ Division of Oncology, Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, PA, USA; Department of Pediatrics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
¹⁰ Division of Hematology/Oncology, Department of Medicine, University of California, San Francisco, San Francisco, CA, USA; Helen Diller Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA. Electronic address: catherine.smith@ucsf.edu.

Abstract

Mutations in the receptor tyrosine kinases (RTKs) FLT3 and KIT are frequent and associated with poor outcomes in acute myeloid leukemia (AML). Although selective 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 the 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 suppresses proliferation of AML cell lines with FLT3 and KIT mutations, including cell lines with acquired resistance to FLT3i. We demonstrate that pharmacologic SHP2 inhibition unveils an Achilles' heel of RTK-driven 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 AML cell lines and in clinically relevant xenograft models. Our results provide mechanistic rationale and pre-clinical evidence for co-targeting SHP2 and BCL2 in RTK-driven AML.

Keywords: FLT3; SHP2; acute myeloid leukemia; apoptosis; cancer; drug synergy; targeted therapies.

Publication types

Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural

MeSH terms

Apoptosis*
Cell Line, Tumor
Humans
Leukemia, Myeloid, Acute* / drug therapy
Leukemia, Myeloid, Acute* / genetics
Leukemia, Myeloid, Acute* / metabolism
Protein Kinase Inhibitors / pharmacology
Proto-Oncogene Proteins c-bcl-2 / genetics
Proto-Oncogene Proteins c-bcl-2 / metabolism
fms-Like Tyrosine Kinase 3 / genetics
fms-Like Tyrosine Kinase 3 / pharmacology

Substances

venetoclax
Protein Kinase Inhibitors
Proto-Oncogene Proteins c-bcl-2
FLT3 protein, human
fms-Like Tyrosine Kinase 3
BCL2 protein, human

Abstract

Publication types

MeSH terms

Substances

Grants and funding