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Allosteric SHP2 inhibition increases apoptotic dependency on BCL2 and synergizes with venetoclax in FLT3- and KIT-mutant AML.
Popescu, Bogdan; Stahlhut, Carlos; Tarver, Theodore C; Wishner, Sydney; Lee, Bianca J; Peretz, Cheryl A C; Luck, Cuyler; Phojanakong, Paul; Camara Serrano, Juan Antonio; Hongo, Henry; Rivera, Jose M; Xirenayi, Simayijiang; Chukinas, John A; Steri, Veronica; Tasian, Sarah K; Stieglitz, Elliot; Smith, Catherine C.
Afiliación
  • Popescu B; 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.
  • Stahlhut C; Revolution Medicines, Inc., Redwood City, CA, USA.
  • Tarver TC; Division of Hematology/Oncology, Department of Medicine, University of California, San Francisco, San Francisco, CA, USA.
  • Wishner S; Division of Hematology/Oncology, Department of Medicine, University of California, San Francisco, San Francisco, CA, USA.
  • Lee BJ; Revolution Medicines, Inc., Redwood City, CA, USA.
  • Peretz CAC; 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.
  • Luck C; Department of Medicine, University of California, San Francisco, San Francisco, CA, USA.
  • Phojanakong P; 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.
  • Camara Serrano JA; 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.
  • Hongo H; Helen Diller Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA.
  • Rivera JM; Helen Diller Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA.
  • Xirenayi S; Helen Diller Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA.
  • Chukinas JA; Division of Oncology, Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
  • Steri V; 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.
  • Tasian SK; 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.
  • Stieglitz E; 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.
  • Smith CC; 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.
Cell Rep Med ; 4(11): 101290, 2023 11 21.
Article en En | MEDLINE | ID: mdl-37992684
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.
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Texto completo: 1 Base de datos: MEDLINE Asunto principal: Leucemia Mieloide Aguda / Apoptosis Límite: Humans Idioma: En Revista: Cell Rep Med Año: 2023 Tipo del documento: Article País de afiliación: Rumanía
Texto completo
Imprimir
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PubMed Links
Buscar en Google

Texto completo: 1 Base de datos: MEDLINE Asunto principal: Leucemia Mieloide Aguda / Apoptosis Límite: Humans Idioma: En Revista: Cell Rep Med Año: 2023 Tipo del documento: Article País de afiliación: Rumanía