Reference Detail

Ref Type

Journal Article

PMID

(37992684)

Authors

Popescu B, Stahlhut C, Tarver TC, Wishner S, Lee BJ, Peretz CAC, Luck C, Phojanakong P, Camara Serrano JA, Hongo H, Rivera JM, Xirenayi S, Chukinas JA, Steri V, Tasian SK, Stieglitz E, Smith CC

Title

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

Journal	Vol	Issue	Date	Pages	Journal Short Title
Cell reports. Medicine	4	11	2023 Nov 21	101290	Cell Rep Med

URL

Abstract Text

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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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
FLT3 exon 14 ins	acute myeloid leukemia	sensitive	RMC-4550	Preclinical - Cell culture	Actionable	In a preclinical study, RMC-4550 inhibited viability in acute myeloid leukemia cell lines harboring FLT3 ITD in culture (PMID: 37992684).	37992684
KIT N822K	acute myeloid leukemia	decreased response	RMC-4550	Preclinical - Cell culture	Actionable	In a preclinical study, acute myeloid leukemia cell lines harboring KIT N822K demonstrated decreased sensitivity to RMC-4550 treatment compared to cell lines harboring FLT3 ITD in culture (PMID: 37992684).	37992684
FLT3 exon 14 ins	acute myeloid leukemia	sensitive	Trametinib + Venetoclax	Preclinical - Cell culture	Actionable	In a preclinical study, the combination of Venclexta (venetoclax) and Mekinist (trametinib) synergistically inhibited proliferation in acute myeloid leukemia cell lines harboring FLT3 ITD in culture (PMID: 37992684).	37992684
FLT3 exon 14 ins NRAS G12C	acute myeloid leukemia	sensitive	RMC-4550 + Venetoclax	Preclinical - Cell line xenograft	Actionable	In a preclinical study, the combination of RMC-4550 and Venclexta (venetoclax) synergistically inhibited viability and induced apoptosis in an acute myeloid leukemia cell line harboring FLT3 ITD and NRAS G12C in culture, and reduced tumor burden and improved survival in a cell line xenograft model (PMID: 37992684).	37992684
NRAS G12D	acute myeloid leukemia	resistant	RMC-4550	Preclinical - Cell culture	Actionable	In a preclinical study, an acute myeloid leukemia cell line harboring NRAS G12D was resistant to RMC-4550 treatment in culture (PMID: 37992684).	37992684
FLT3 exon 14 ins NRAS G12C	acute myeloid leukemia	sensitive	Gilteritinib + RMC-4550	Preclinical - Cell culture	Actionable	In a preclinical study, the combination of RMC-4550 and Xospata (gilteritinib) inhibited viability in an acute myeloid leukemia cell line harboring FLT3 ITD and NRAS G12C in culture (PMID: 37992684).	37992684
FLT3 exon 14 ins FLT3 D835H	acute myeloid leukemia	sensitive	RMC-4550	Preclinical - Cell culture	Actionable	In a preclinical study, RMC-4550 inhibited viability in an acute myeloid leukemia cell line harboring FLT3 ITD and expressing FLT3 D835H in culture (PMID: 37992684).	37992684
KIT N822K	acute myeloid leukemia	sensitive	Trametinib + Venetoclax	Preclinical - Cell culture	Actionable	In a preclinical study, the combination of Venclexta (venetoclax) and Mekinist (trametinib) synergistically inhibited proliferation in acute myeloid leukemia cell lines harboring KIT N822K in culture (PMID: 37992684).	37992684
FLT3 exon 14 ins NRAS Q61K	acute myeloid leukemia	resistant	RMC-4550	Preclinical - Cell culture	Actionable	In a preclinical study, an acute myeloid leukemia cell line harboring FLT3 ITD and expressing NRAS Q61K was resistant to RMC-4550 treatment in culture (PMID: 37992684).	37992684
FLT3 exon 14 ins FLT3 D835Y	acute myeloid leukemia	sensitive	RMC-4550	Preclinical - Cell culture	Actionable	In a preclinical study, RMC-4550 inhibited viability in an acute myeloid leukemia cell line harboring FLT3 ITD and expressing FLT3 D835Y in culture (PMID: 37992684).	37992684
FLT3 exon 14 ins FLT3 Y842C	acute myeloid leukemia	sensitive	RMC-4550	Preclinical - Cell culture	Actionable	In a preclinical study, RMC-4550 inhibited viability in an acute myeloid leukemia cell line harboring FLT3 ITD and expressing FLT3 Y842C in culture (PMID: 37992684).	37992684
KIT N822K	acute myeloid leukemia	sensitive	RMC-4550 + Venetoclax	Preclinical - Cell line xenograft	Actionable	In a preclinical study, the combination of RMC-4550 and Venclexta (venetoclax) synergistically inhibited viability and induced apoptosis in an acute myeloid leukemia cell line harboring KIT N822K in culture, and reduced tumor burden and improved survival in a cell line xenograft model (PMID: 37992684).	37992684
FLT3 exon 14 ins	acute myeloid leukemia	sensitive	RMC-4550 + Venetoclax	Preclinical - Pdx & cell culture	Actionable	In a preclinical study, the combination of RMC-4550 and Venclexta (venetoclax) synergistically inhibited viability and induced apoptosis in acute myeloid leukemia cell lines harboring FLT3 ITD in culture, reduced tumor burden and improved survival in a cell line xenograft model, and reduced leukemia burden in a patient-derived xenograft (PDX) model (PMID: 37992684).	37992684
NRAS Q61L	acute myeloid leukemia	resistant	RMC-4550	Preclinical - Cell culture	Actionable	In a preclinical study, acute myeloid leukemia cell lines harboring NRAS Q61L were resistant to RMC-4550 treatment in culture (PMID: 37992684).	37992684
FLT3 exon 14 ins FLT3 N841K	acute myeloid leukemia	sensitive	RMC-4550	Preclinical - Cell culture	Actionable	In a preclinical study, RMC-4550 inhibited viability in an acute myeloid leukemia cell line harboring FLT3 ITD and expressing FLT3 N841K in culture (PMID: 37992684).	37992684
FLT3 exon 14 ins NRAS G12C	acute myeloid leukemia	sensitive	RMC-4550	Preclinical - Cell culture	Actionable	In a preclinical study, RMC-4550 inhibited viability in an acute myeloid leukemia cell line harboring FLT3 ITD and NRAS G12C in culture (PMID: 37992684).	37992684
FLT3 exon 14 ins NRAS Q61K	acute myeloid leukemia	resistant	Gilteritinib + RMC-4550	Preclinical - Cell culture	Actionable	In a preclinical study, an acute myeloid leukemia cell line harboring FLT3 ITD and NRAS Q61K was resistant to the combination of RMC-4550 and Xospata (gilteritinib) in culture (PMID: 37992684).	37992684
FLT3 exon 14 ins FLT3 F691L	acute myeloid leukemia	sensitive	RMC-4550	Preclinical - Cell culture	Actionable	In a preclinical study, RMC-4550 inhibited viability in an acute myeloid leukemia cell line harboring FLT3 ITD and expressing FLT3 F691L in culture (PMID: 37992684).	37992684
FLT3 exon 14 ins FLT3 D835V	acute myeloid leukemia	sensitive	RMC-4550	Preclinical - Cell culture	Actionable	In a preclinical study, RMC-4550 inhibited viability in an acute myeloid leukemia cell line harboring FLT3 ITD and expressing FLT3 D835V in culture (PMID: 37992684).	37992684