Molecule Information

General Information of the Molecule (ID: Mol04338)

• Name: Serine/threonine-protein phosphatase 2B catalytic subunit beta isoform (PPP3CB) ,Homo sapiens
• Synonyms: CAM-PRP catalytic subunit; Calmodulin-dependent calcineurin A subunit beta isoform
• Molecule Type: Protein
• Gene Name: PPP3CB
• Gene ID: 5532
• Sequence:
  MAAPEPARAAPPPPPPPPPPPGADRVVKAVPFPPTHRLTSEEVFDLDGIPRVDVLKNHLV
  KEGRVDEEIALRIINEGAAILRREKTMIEVEAPITVCGDIHGQFFDLMKLFEVGGSPAN
  T RYLFLGDYVDRGYFSIECVLYLWVLKILYPSTLFLLRGNHECRHLTEYFTFKQECKIK
  YS ERVYEACMEAFDSLPLAALLNQQFLCVHGGLSPEIHTLDDIRRLDRFKEPPAFGPMC
  DLL WSDPSEDFGNEKSQEHFSHNTVRGCSYFYNYPAVCEFLQNNNLLSIIRAHEAQDAG
  YRMY RKSQTTGFPSLITIFSAPNYLDVYNNKAAVLKYENNVMNIRQFNCSPHPYWLPNF
  MDVFT WSLPFVGEKVTEMLVNVLSICSDDELMTEGEDQFDGSAAARKEIIRNKIRAIGK
  MARVFS VLREESESVLTLKGLTPTGMLPSGVLAGGRQTLQSATVEAIEAEKAIRGFSPP
  HRICSFE EAKGLDRINERMPPRKDAVQQDGFNSLNTAHATENHGTGNHTAQ
• Function: Calcium-dependent, calmodulin-stimulated protein phosphatasewhich plays an essential role in the transduction of intracellularCa-mediated signals . Dephosphorylates TFEB in response tolysosomal Ca release, resulting in TFEB nuclear translocation andstimulation of lysosomal biogenesis .Dephosphorylates and activates transcription factor NFATC1. Dephosphorylates and inactivates transcriptionfactor ELK1 . Dephosphorylates DARPP32. Negatively regulates MAP3K14/NIK signaling viainhibition of nuclear translocation of the transcription factors RELAand RELB . May play a role in skeletal muscle fiber typespecification . {ECO:0000250|UniProtKB:P48453,ECO:0000269|PubMed:19154138, ECO:0000269|PubMed:25720963,ECO:0000269|PubMed:26794871, ECO:0000269|PubMed:32753672}.
• Uniprot ID: PP2BB_HUMAN
• Ensembl ID: ENSG0000010775816
• HGNC ID: HGNC:9315

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

Type(s) of Resistant Mechanism of This Molecule

  UAPP: Unusual Activation of Pro-survival Pathway

Drug Resistance Data Categorized by Drug

Approved Drug(s) 3 drug(s) in total

Dacomitinib

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Lung adenocarcinoma [ICD-11: 2C25.0] [1]

• Resistant Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Resistant Drug: Dacomitinib
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Ca2+/calcineurin/MEK/ERK1/2 signaling pathway; Regulation; N.A.
• In Vitro Model: PC9/DR cells; N.A.; Homo sapiens (Human); N.A.
• In Vitro Model: PC9/GR cells; N.A.; Homo sapiens (Human); N.A.
• In Vitro Model: PC9/OR cells; N.A.; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Western blot assay
• Experiment for Drug Resistance: MTS assay; Flow cytometric assay; Colony formation assay
• Mechanism Description: Here, we show that a?PPP3CB?transcript that encodes full-length catalytic subunit 2B of calcineurin accumulates in EGFR-mutant NSCLC cells with acquired resistance against different EGFR TKIs and in post-progression biopsies of NSCLC patients treated with EGFR TKIs. Neutralization of?PPP3CB?by siRNA or inactivation of calcineurin by cyclosporin A induces apoptosis in resistant cells treated with EGFR TKIs. Mechanistically, EGFR TKIs increase the cytosolic level of calcium and trigger activation of a calcineurin/MEK/ERK pathway that prevents apoptosis. Combining EGFR, calcineurin, and MEK inhibitors overcomes resistance to EGFR TKI in both in vitro and in vivo models. Our results identify PPP3CB overexpression as a new mechanism of acquired resistance to EGFR TKIs, and provide a promising therapeutic approach for NSCLC patients that progress under TKI treatment.

Gefitinib

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Lung adenocarcinoma [ICD-11: 2C25.0] [1]

• Resistant Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Resistant Drug: Gefitinib
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Ca2+/calcineurin/MEK/ERK1/2 signaling pathway; Regulation; N.A.
• In Vitro Model: PC9/DR cells; N.A.; Homo sapiens (Human); N.A.
• In Vitro Model: PC9/GR cells; N.A.; Homo sapiens (Human); N.A.
• In Vitro Model: PC9/OR cells; N.A.; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Western blot assay
• Experiment for Drug Resistance: MTS assay; Flow cytometric assay; Colony formation assay
• Mechanism Description: Here, we show that a?PPP3CB?transcript that encodes full-length catalytic subunit 2B of calcineurin accumulates in EGFR-mutant NSCLC cells with acquired resistance against different EGFR TKIs and in post-progression biopsies of NSCLC patients treated with EGFR TKIs. Neutralization of?PPP3CB?by siRNA or inactivation of calcineurin by cyclosporin A induces apoptosis in resistant cells treated with EGFR TKIs. Mechanistically, EGFR TKIs increase the cytosolic level of calcium and trigger activation of a calcineurin/MEK/ERK pathway that prevents apoptosis. Combining EGFR, calcineurin, and MEK inhibitors overcomes resistance to EGFR TKI in both in vitro and in vivo models. Our results identify PPP3CB overexpression as a new mechanism of acquired resistance to EGFR TKIs, and provide a promising therapeutic approach for NSCLC patients that progress under TKI treatment.

Osimertinib

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Lung adenocarcinoma [ICD-11: 2C25.0] [1]

• Resistant Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Resistant Drug: Osimertinib
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Ca2+/calcineurin/MEK/ERK1/2 signaling pathway; Regulation; N.A.
• In Vivo Model: Patient-derived EGFR-mutant lung adenocarcinoma model; Homo sapiens
• Experiment for Molecule Alteration: Western blot assay
• Mechanism Description: Here, we show that a?PPP3CB?transcript that encodes full-length catalytic subunit 2B of calcineurin accumulates in EGFR-mutant NSCLC cells with acquired resistance against different EGFR TKIs and in post-progression biopsies of NSCLC patients treated with EGFR TKIs. Neutralization of?PPP3CB?by siRNA or inactivation of calcineurin by cyclosporin A induces apoptosis in resistant cells treated with EGFR TKIs. Mechanistically, EGFR TKIs increase the cytosolic level of calcium and trigger activation of a calcineurin/MEK/ERK pathway that prevents apoptosis. Combining EGFR, calcineurin, and MEK inhibitors overcomes resistance to EGFR TKI in both in vitro and in vivo models. Our results identify PPP3CB overexpression as a new mechanism of acquired resistance to EGFR TKIs, and provide a promising therapeutic approach for NSCLC patients that progress under TKI treatment.

Disease Class: Lung adenocarcinoma [ICD-11: 2C25.0] [1]

• Resistant Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Resistant Drug: Osimertinib
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Ca2+/calcineurin/MEK/ERK1/2 signaling pathway; Regulation; N.A.
• In Vitro Model: PC9/DR cells; N.A.; Homo sapiens (Human); N.A.
• In Vitro Model: PC9/GR cells; N.A.; Homo sapiens (Human); N.A.
• In Vitro Model: PC9/OR cells; N.A.; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Western blot assay
• Experiment for Drug Resistance: MTS assay; Flow cytometric assay; Colony formation assay
• Mechanism Description: Here, we show that a?PPP3CB?transcript that encodes full-length catalytic subunit 2B of calcineurin accumulates in EGFR-mutant NSCLC cells with acquired resistance against different EGFR TKIs and in post-progression biopsies of NSCLC patients treated with EGFR TKIs. Neutralization of?PPP3CB?by siRNA or inactivation of calcineurin by cyclosporin A induces apoptosis in resistant cells treated with EGFR TKIs. Mechanistically, EGFR TKIs increase the cytosolic level of calcium and trigger activation of a calcineurin/MEK/ERK pathway that prevents apoptosis. Combining EGFR, calcineurin, and MEK inhibitors overcomes resistance to EGFR TKI in both in vitro and in vivo models. Our results identify PPP3CB overexpression as a new mechanism of acquired resistance to EGFR TKIs, and provide a promising therapeutic approach for NSCLC patients that progress under TKI treatment.

References

• Ref 1: PPP3CB overexpression mediates EGFR TKI resistance in lung tumors via calcineurin/MEK/ERK signaling. Life Sci Alliance. 2024 Oct 1;7(12):e202402873.