Disease Information

General Information of the Disease (ID: DIS00501)

• Name: Acute lymphocytic leukemia
• ICD: ICD-11: 2B33

Type(s) of Resistant Mechanism of This Disease

  DISM: Drug Inactivation by Structure Modification

  IDUE: Irregularity in Drug Uptake and Drug Efflux

  MRAP: Metabolic Reprogramming via Altered Pathways

Drug Resistance Data Categorized by Drug

Approved Drug(s) 2 drug(s) in total

L-asparaginase

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Metabolic Reprogramming via Altered Pathways (MRAP)

Key Molecule: Glutamine synthetase (GLUL) [2]

• Metabolic Type: Glutamine metabolism
• Resistant Disease: Acute lymphoblastic leukemia [ICD-11: 2B33.3]
• Resistant Drug: L-asparaginase
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: Capan-1 cells; Pancreas; Homo sapiens (Human); CVCL_0237
• In Vitro Model: MiaPaCa-2 cells; Blood; Homo sapiens (Human); CVCL_0428
• In Vitro Model: Panc1 cells; Pancreas; Homo sapiens (Human); CVCL_0480
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: By developing l-Asparaginase-resistant Pancreatic Cancercells and using OMICS approaches, we identified glutamine synthetase (GS) as a marker of resistance to l-Asparaginase. GS is the only enzyme able to synthesize glutamine, and its expression also correlates with l-Asparaginase efficacy in 27 human cell lines from 11 cancer indications. Finally, we further demonstrated that GS inhibition prevents cancer cell adaptation to l-Asparaginase-induced glutamine starvation.

Raltitrexed

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Gamma-glutamyl hydrolase (GGH) [3]

• Resistant Disease: Acute lymphoblastic leukemia [ICD-11: 2B33.3]
• Resistant Drug: Raltitrexed
• Molecule Alteration: Mutations; G667C; F589L-G595R
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: GGH signaling pathway; Regulation; N.A.
• In Vitro Model: REH cells; Bone marrow; Homo sapiens (Human); CVCL_1650
• In Vitro Model: Nalm-6 cells; Peripheral blood; Homo sapiens (Human); CVCL_0092
• Experiment for Molecule Alteration: Immunofluorescence staining assay; Western blot assay
• Experiment for Drug Resistance: Cell viability assay; MTX polyglutamated metabolite assay; Folate growth requirement assay
• Mechanism Description: A key cofactor of several enzymes implicated in DNA synthesis, repair, and methylation, folate has been shown to be required for normal cell growth and replication and is the basis for cancer chemotherapy using antifolates. gamma-Glutamyl hydrolase (GGH) catalyzes the removal of gamma-polyglutamate tails of folylpoly-/antifolylpoly-gamma-glutamates to facilitate their export out of the cell, thereby maintaining metabolic homeostasis of folates or pharmacological efficacy of antifolates. However, the factors that control or modulate GGH function are not well understood. In this study, we show that intact GGH is not indispensable for the chemosensitivity and growth of acute lymphoblastic leukemia (ALL) cells, whereas GGH lacking N-terminal signal peptide (GGH?deltaN) confers the significant drug resistance of ALL cells to the antifolates MTX and RTX. In addition, ALL cells harboring GGH?deltaN show high susceptibility to the change in folates, and glycosylation is not responsible for these phenotypes elicited by GGH?deltaN. Mechanistically, the loss of signal peptide enhances intracellular retention of GGH and its lysosomal disposition.

Clinical Trial Drug(s) 1 drug(s) in total

Tanespimycin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: ATP-dependent translocase ABCB1 (ABCB1) [1]

• Resistant Disease: Acute lymphoblastic leukemia [ICD-11: 2B33.3]
• Resistant Drug: Tanespimycin
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: K562 cells; Blood; Homo sapiens (Human); CVCL_0004
• In Vitro Model: kCL22 cells; Pleural effusion; Homo sapiens (Human); CVCL_2091
• In Vitro Model: Sup-B15 cells; Bone marrow; Homo sapiens (Human); CVCL_0103
• In Vivo Model: NSG mice model; Mus musculus
• Experiment for Molecule Alteration: Immunofluorescence staining assay; Western blot assay
• Experiment for Drug Resistance: Colony forming unit assay; Caspase 3/7 Glo assay
• Mechanism Description: Tanespimycin and Coumermycin A1 was attained by MDR1 efflux pump overexpression.

References

• Ref 1: Co-targeting HSP90 alpha and CDK7 overcomes resistance against HSP90 inhibitors in BCR-ABL1+ leukemia cells. Cell Death Dis. 2023 Dec 6;14(12):799.
• Ref 2: L-asparaginase anti-tumor activity in pancreatic cancer is dependent on its glutaminase activity and resistance is mediated by glutamine synthetase. Exp Cell Res. 2023 May 15;426(2):113568.
• Ref 3: A gamma-glutamyl hydrolase lacking the signal peptide confers susceptibility to folates/antifolates in acute lymphoblastic leukemia cells. FEBS Lett. 2022 Feb;596(4):437-448.