Molecule Information

General Information of the Molecule (ID: Mol04013)

• Name: Aldo-keto reductase family 1 member B10 (AKR1B10) ,Homo sapiens
• Synonyms: ARL-1; Aldose reductase-like; Aldose reductase-related protein; Small intestine reductase
• Molecule Type: Protein
• Gene Name: AKR1B10
• Gene ID: 57016
• Location: chr7:134527567-134541412[+]
• Sequence:
  MATFVELSTKAKMPIVGLGTWKSPLGKVKEAVKVAIDAGYRHIDCAYVYQNEHEVGEAIQ
  EKIQEKAVKREDLFIVSKLWPTFFERPLVRKAFEKTLKDLKLSYLDVYLIHWPQGFKSGD
  DLFPKDDKGNAIGGKATFLDAWEAMEELVDEGLVKALGVSNFSHFQIEKLLNKPGLKYKP
  VTNQVECHPYLTQEKLIQYCHSKGITVTAYSPLGSPDRPWAKPEDPSLLEDPKIKEIAAK
  HKKTAAQVLIRFHIQRNVIVIPKSVTPARIVENIQVFDFKLSDEEMATILSFNRNWRACN
  VLQSSHLEDYPFNAEY
• 3D-structure: PDB ID: 4GQG; Classification: Oxidoreductase; Method: X-ray diffraction; Resolution: 1.92 Å
• Function: Catalyzes the NADPH-dependent reduction of a wide variety of carbonyl-containing compounds to their corresponding alcohols (PubMed:12732097, PubMed:18087047, PubMed:19013440, PubMed:19563777, PubMed:9565553). Displays strong enzymatic activity toward all-trans- retinal, 9-cis-retinal, and 13-cis-retinal (PubMed:12732097, PubMed:18087047). Plays a critical role in detoxifying dietary and lipid-derived unsaturated carbonyls, such as crotonaldehyde, 4- hydroxynonenal, trans-2-hexenal, trans-2,4-hexadienal and their glutathione-conjugates carbonyls (GS-carbonyls) (PubMed:19013440, PubMed:19563777). Displays no reductase activity towards glucose (PubMed:12732097). .
• Uniprot ID: AK1BA_HUMAN
• Ensembl ID: ENSG00000198074
• HGNC ID: HGNC:382

Kingdom: Metazoa
Phylum: Chordata
Class: Mammalia
Order: Primates
Family: Hominidae
Genus: Homo
Species: Homo sapiens

Type(s) of Resistant Mechanism of This Molecule

  DISM: Drug Inactivation by Structure Modification

  MRAP: Metabolic Reprogramming via Altered Pathways

Drug Resistance Data Categorized by Drug

Approved Drug(s) 4 drug(s) in total

Pemetrexed

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Metabolic Reprogramming via Altered Pathways (MRAP)

Disease Class: Lung cancer brain metastasis [ICD-11: 2C25.3] [1]

• Metabolic Type: Glucose metabolism
• Sensitive Disease: Lung cancer brain metastasis [ICD-11: 2C25.3]
• Sensitive Drug: Pemetrexed
• Molecule Alteration: Expression; Up-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Lung cancer [ICD-11: 2C25]
• The Specified Disease: Lung cancer brain metastasis
• The Studied Tissue: Lung tissue
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 1.92E-01; Fold-change: 2.98E-01; Z-score: 1.31E+00
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: AKR1B10 knockdown PC9-BrM3 cells; Lung; Homo sapiens (Human); CVCL_XA19
• Experiment for Drug Resistance: Cell viability assay; Clonogenicity assay; Cell apoptosis assay
• Mechanism Description: Metabolic profiling revealed that AKR1B10 prominently facilitated the Warburg metabolism characterized by the overproduction of lactate. Glycolysis regulated by AKR1B10 is vital for the resistance to PEM. In mechanism, AKR1B10 promoted glycolysis by regulating the expression of lactate dehydrogenase (LDHA) and the increased lactate, acts as a precursor that stimulates histone lactylation (H4K12la), activated the transcription of CCNB1 and accelerated the DNA replication and cell cycle.

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Metabolic Reprogramming via Altered Pathways (MRAP)

Disease Class: Lung cancer brain metastasis [ICD-11: 2C25.3] [1]

• Metabolic Type: Glucose metabolism
• Resistant Disease: Lung cancer brain metastasis [ICD-11: 2C25.3]
• Resistant Drug: Pemetrexed
• Molecule Alteration: Expression; Up-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Lung cancer [ICD-11: 2C25]
• The Specified Disease: Lung cancer brain metastasis
• The Studied Tissue: Lung tissue
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 1.92E-01; Fold-change: 2.98E-01; Z-score: 1.31E+00
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: Highly brain metastatic lung cancer PC9-BrM3 cells; Lung; Homo sapiens (Human); CVCL_XA19
• Experiment for Drug Resistance: Cell viability assay; Cell colony formation assay
• Mechanism Description: Metabolic profiling revealed that AKR1B10 prominently facilitated the Warburg metabolism characterized by the overproduction of lactate. Glycolysis regulated by AKR1B10 is vital for the resistance to PEM. In mechanism, AKR1B10 promoted glycolysis by regulating the expression of lactate dehydrogenase (LDHA) and the increased lactate, acts as a precursor that stimulates histone lactylation (H4K12la), activated the transcription of CCNB1 and accelerated the DNA replication and cell cycle.

Carboplatin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Disease Class: Lung adenocarcinoma [ICD-11: 2C25.0] [2]

• Resistant Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Resistant Drug: Carboplatin
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vivo Model: MU375/MU383 patient-derived tumor organoids; Homo sapiens
• Experiment for Molecule Alteration: qPCR; IHC assay
• Experiment for Drug Resistance: Drug sensitivity testing
• Mechanism Description: Epalrestat can be repurposed to overcome chemoresistance. PDTOs retained histomorphology and pathological biomarker expression, mutational/transcriptomic signatures, and cellular heterogeneity of the matched tumor tissues. Five (50%) PDTOs were chemoresistant toward carboplatin/paclitaxel. Chemoresistant PDTOs and matched tumor tissues demonstrated overexpression of AKR1B10. Epalrestat, an orally available AKR1B10 inhibitor in clinical use for diabetic polyneuropathy, was repurposed to overcome chemoresistance of PDTOs. In vivo efficacy of epalrestat to overcome drug resistance corresponded to intratumoral epalrestat levels.

Epalrestat

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Disease Class: Lung adenocarcinoma [ICD-11: 2C25.0] [2]

• Sensitive Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Sensitive Drug: Epalrestat
• Molecule Alteration: Expression; .
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vivo Model: MU375/MU383 patient-derived tumor organoids; Homo sapiens
• Experiment for Molecule Alteration: qPCR; IHC assay
• Experiment for Drug Resistance: Drug sensitivity testing
• Mechanism Description: Epalrestat can be repurposed to overcome chemoresistance. PDTOs retained histomorphology and pathological biomarker expression, mutational/transcriptomic signatures, and cellular heterogeneity of the matched tumor tissues. Five (50%) PDTOs were chemoresistant toward carboplatin/paclitaxel. Chemoresistant PDTOs and matched tumor tissues demonstrated overexpression of AKR1B10. Epalrestat, an orally available AKR1B10 inhibitor in clinical use for diabetic polyneuropathy, was repurposed to overcome chemoresistance of PDTOs. In vivo efficacy of epalrestat to overcome drug resistance corresponded to intratumoral epalrestat levels.

Paclitaxel

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Disease Class: Lung adenocarcinoma [ICD-11: 2C25.0] [2]

• Resistant Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Resistant Drug: Paclitaxel
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vivo Model: MU375/MU383 patient-derived tumor organoids; Homo sapiens
• Experiment for Molecule Alteration: qPCR; IHC assay
• Experiment for Drug Resistance: Drug sensitivity testing
• Mechanism Description: Epalrestat can be repurposed to overcome chemoresistance. PDTOs retained histomorphology and pathological biomarker expression, mutational/transcriptomic signatures, and cellular heterogeneity of the matched tumor tissues. Five (50%) PDTOs were chemoresistant toward carboplatin/paclitaxel. Chemoresistant PDTOs and matched tumor tissues demonstrated overexpression of AKR1B10. Epalrestat, an orally available AKR1B10 inhibitor in clinical use for diabetic polyneuropathy, was repurposed to overcome chemoresistance of PDTOs. In vivo efficacy of epalrestat to overcome drug resistance corresponded to intratumoral epalrestat levels.

References

• Ref 1: Warburg effect enhanced by AKR1B10 promotes acquired resistance to pemetrexed in lung cancer-derived brain metastasis. J Transl Med. 2023 Aug 16;21(1):547.
• Ref 2: Targeting AKR1B10 by Drug Repurposing with Epalrestat Overcomes Chemoresistance in Non-Small Cell Lung Cancer Patient-Derived Tumor Organoids. Clin Cancer Res. 2024 Sep 3;30(17):3855-3867.