Molecule Information

General Information of the Molecule (ID: Mol01843)

• Name: Serine/threonine-protein kinase STK11 (STK11) ,Homo sapiens
• Synonyms: Serine/threonine-protein kinase STK11; (Liver kinase B1; LKB1; hLKB1; Renal carcinoma antigen NY-REN-19
• Molecule Type: Protein
• Gene Name: STK11
• Gene ID: 6794
• Location: chr19:1,177,558-1,228,431[+]
• Sequence:
  MEVVDPQQLGMFTEGELMSVGMDTFIHRIDSTEVIYQPRRKRAKLIGKYLMGDLLGEGSY
  GKVKEVLDSETLCRRAVKILKKKKLRRIPNGEANVKKEIQLLRRLRHKNVIQLVDVLYNE
  EKQKMYMVMEYCVCGMQEMLDSVPEKRFPVCQAHGYFCQLIDGLEYLHSQGIVHKDIKPG
  NLLLTTGGTLKISDLGVAEALHPFAADDTCRTSQGSPAFQPPEIANGLDTFSGFKVDIWS
  AGVTLYNITTGLYPFEGDNIYKLFENIGKGSYAIPGDCGPPLSDLLKGMLEYEPAKRFSI
  RQIRQHSWFRKKHPPAEAPVPIPPSPDTKDRWRSMTVVPYLEDLHGADEDEDLFDIEDDI
  IYTQDFTVPGQVPEEEASHNGQRRGLPKAVCMNGTEAAQLSTKSRAEGRAPNPARKACSA
  SSKIRRLSACKQQ
• Function: Tumor suppressor serine/threonine-protein kinase that controls the activity of AMP-activated protein kinase (AMPK) family members, thereby playing a role in various processes such as cell metabolism, cell polarity, apoptosis and DNA damage response. Acts by phosphorylating the T-loop of AMPK family proteins, thus promoting their activity: phosphorylates PRKAA1, PRKAA2, BRSK1, BRSK2, MARK1, MARK2, MARK3, MARK4, NUAK1, NUAK2, SIK1, SIK2, SIK3 and SNRK but not MELK. Also phosphorylates non-AMPK family proteins such as STRADA, PTEN and possibly p53/TP53. Acts as a key upstream regulator of AMPK by mediating phosphorylation and activation of AMPK catalytic subunits PRKAA1 and PRKAA2 and thereby regulates processes including: inhibition of signaling pathways that promote cell growth and proliferation when energy levels are low, glucose homeostasis in liver, activation of autophagy when cells undergo nutrient deprivation, and B-cell differentiation in the germinal center in response to DNA damage. Also acts as a regulator of cellular polarity by remodeling the actin cytoskeleton. Required for cortical neuron polarization by mediating phosphorylation and activation of BRSK1 and BRSK2, leading to axon initiation and specification. Involved in DNA damage response: interacts with p53/TP53 and recruited to the CDKN1A/WAF1 promoter to participate in transcription activation. Able to phosphorylate p53/TP53; the relevance of such result in vivo is however unclear and phosphorylation may be indirect and mediated by downstream STK11/LKB1 kinase NUAK1. Also acts as a mediator of p53/TP53-dependent apoptosis via interaction with p53/TP53: translocates to the mitochondrion during apoptosis and regulates p53/TP53-dependent apoptosis pathways. Regulates UV radiation-induced DNA damage response mediated by CDKN1A. In association with NUAK1, phosphorylates CDKN1A in response to UV radiation and contributes to its degradation which is necessary for optimal DNA repair.
• Uniprot ID: STK11_HUMAN
• Ensembl ID: ENSG00000118046
• HGNC ID: HGNC:11389

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) 2 drug(s) in total

Durvalumab

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Non-small cell lung cancer [1]

• Resistant Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Resistant Drug: Durvalumab
• Molecule Alteration: Mutation; .
• Experimental Note: Discovered Using In-vivo Testing Model
• Cell Pathway Regulation: STAT3 signaling pathway; Activation; hsa04550
• In Vitro Model: 4T1-Luc2 cells; Mammary gland; Mus musculus (Mouse); CVCL_A4BM
• In Vitro Model: CD138+ myeloma cells; Pleural effusion; Homo sapiens (Human); N.A.
• In Vitro Model: HTH7 cells; Thyroid gland; Homo sapiens (Human); CVCL_6289
• In Vitro Model: EMT6 WT cells; Breast; Mus musculus (Mouse); CVCL_1923
• In Vivo Model: Mouse tumor model; Mus musculus
• Experiment for Drug Resistance: Flow cytometry
• Mechanism Description: Resistance to Durvalumab and Durvalumab plus Tremelimumab Is Associated with Functional STK11 Mutations in Patients with Non-Small Cell Lung Cancer and Is Reversed by STAT3 Knockdown.

Trametinib

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Lung adenocarcinoma [2]

• Sensitive Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Sensitive Drug: Trametinib
• Molecule Alteration: Nonsense; p.Q37* (c.109C>T)
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: MEK signaling pathway; Inhibition; hsa04011
• In Vitro Model: H292 cells; Lung; Homo sapiens (Human); CVCL_0455
• In Vitro Model: H1299 cells; Lung; Homo sapiens (Human); CVCL_0060
• In Vitro Model: H157 cells; Lung; Homo sapiens (Human); CVCL_2458
• In Vitro Model: H23 cells; Lung; Homo sapiens (Human); CVCL_1547
• In Vitro Model: Calu-3 cells; Lung; Homo sapiens (Human); CVCL_0609
• In Vitro Model: HCC78 cells; Pleural effusion; Homo sapiens (Human); CVCL_2061
• In Vitro Model: HCC515 cells; Lymph node; Homo sapiens (Human); CVCL_5136
• In Vitro Model: HCC2935 cells; Lung; Homo sapiens (Human); CVCL_1265
• In Vitro Model: HCC193 cells; Lung; Homo sapiens (Human); CVCL_5130
• In Vitro Model: HCC15 cells; Lung; Homo sapiens (Human); CVCL_2057
• In Vitro Model: H520 cells; Lung; Homo sapiens (Human); CVCL_1566
• In Vitro Model: H2126 cells; Pleural effusion; Homo sapiens (Human); CVCL_1532
• In Vitro Model: H2122 cells; Pleural effusion; Homo sapiens (Human); CVCL_1531
• In Vitro Model: H2085 cells; Lung; Homo sapiens (Human); CVCL_1523
• In Vitro Model: H1993 cells; Lymph node; Homo sapiens (Human); CVCL_1512
• In Vitro Model: H1435 cells; Lung; Homo sapiens (Human); CVCL_1470
• In Vitro Model: H1395 cells; Lung; Homo sapiens (Human); CVCL_1467
• In Vitro Model: H1355 cells; Pleural effusion; Homo sapiens (Human); CVCL_1464
• In Vitro Model: Calu-6 cells; Lung; Homo sapiens (Human); CVCL_0236
• In Vitro Model: Calu-1 cells; Lung; Homo sapiens (Human); CVCL_0608
• In Vivo Model: NOD-SCID mouse PDX model; Mus musculus
• Experiment for Molecule Alteration: Immunoblotting analysis
• Experiment for Drug Resistance: Alamar blue proliferation assay

Disease Class: Lung adenocarcinoma [2]

• Sensitive Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Sensitive Drug: Trametinib
• Molecule Alteration: Nonsense; p.E199* (c.595G>T)
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: MEK signaling pathway; Inhibition; hsa04011
• In Vitro Model: H292 cells; Lung; Homo sapiens (Human); CVCL_0455
• In Vitro Model: H1299 cells; Lung; Homo sapiens (Human); CVCL_0060
• In Vitro Model: H157 cells; Lung; Homo sapiens (Human); CVCL_2458
• In Vitro Model: H23 cells; Lung; Homo sapiens (Human); CVCL_1547
• In Vitro Model: Calu-3 cells; Lung; Homo sapiens (Human); CVCL_0609
• In Vitro Model: HCC78 cells; Pleural effusion; Homo sapiens (Human); CVCL_2061
• In Vitro Model: HCC515 cells; Lymph node; Homo sapiens (Human); CVCL_5136
• In Vitro Model: HCC2935 cells; Lung; Homo sapiens (Human); CVCL_1265
• In Vitro Model: HCC193 cells; Lung; Homo sapiens (Human); CVCL_5130
• In Vitro Model: HCC15 cells; Lung; Homo sapiens (Human); CVCL_2057
• In Vitro Model: H520 cells; Lung; Homo sapiens (Human); CVCL_1566
• In Vitro Model: H2126 cells; Pleural effusion; Homo sapiens (Human); CVCL_1532
• In Vitro Model: H2122 cells; Pleural effusion; Homo sapiens (Human); CVCL_1531
• In Vitro Model: H2085 cells; Lung; Homo sapiens (Human); CVCL_1523
• In Vitro Model: H1993 cells; Lymph node; Homo sapiens (Human); CVCL_1512
• In Vitro Model: H1435 cells; Lung; Homo sapiens (Human); CVCL_1470
• In Vitro Model: H1395 cells; Lung; Homo sapiens (Human); CVCL_1467
• In Vitro Model: H1355 cells; Pleural effusion; Homo sapiens (Human); CVCL_1464
• In Vitro Model: Calu-6 cells; Lung; Homo sapiens (Human); CVCL_0236
• In Vitro Model: Calu-1 cells; Lung; Homo sapiens (Human); CVCL_0608
• In Vivo Model: NOD-SCID mouse PDX model; Mus musculus
• Experiment for Molecule Alteration: Immunoblotting analysis
• Experiment for Drug Resistance: Alamar blue proliferation assay

Disease Class: Lung adenocarcinoma [2]

• Sensitive Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Sensitive Drug: Trametinib
• Molecule Alteration: Nonsense; p.W332* (c.995G>A)
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: MEK signaling pathway; Inhibition; hsa04011
• In Vitro Model: H292 cells; Lung; Homo sapiens (Human); CVCL_0455
• In Vitro Model: H1299 cells; Lung; Homo sapiens (Human); CVCL_0060
• In Vitro Model: H157 cells; Lung; Homo sapiens (Human); CVCL_2458
• In Vitro Model: H23 cells; Lung; Homo sapiens (Human); CVCL_1547
• In Vitro Model: Calu-3 cells; Lung; Homo sapiens (Human); CVCL_0609
• In Vitro Model: HCC78 cells; Pleural effusion; Homo sapiens (Human); CVCL_2061
• In Vitro Model: HCC515 cells; Lymph node; Homo sapiens (Human); CVCL_5136
• In Vitro Model: HCC2935 cells; Lung; Homo sapiens (Human); CVCL_1265
• In Vitro Model: HCC193 cells; Lung; Homo sapiens (Human); CVCL_5130
• In Vitro Model: HCC15 cells; Lung; Homo sapiens (Human); CVCL_2057
• In Vitro Model: H520 cells; Lung; Homo sapiens (Human); CVCL_1566
• In Vitro Model: H2126 cells; Pleural effusion; Homo sapiens (Human); CVCL_1532
• In Vitro Model: H2122 cells; Pleural effusion; Homo sapiens (Human); CVCL_1531
• In Vitro Model: H2085 cells; Lung; Homo sapiens (Human); CVCL_1523
• In Vitro Model: H1993 cells; Lymph node; Homo sapiens (Human); CVCL_1512
• In Vitro Model: H1435 cells; Lung; Homo sapiens (Human); CVCL_1470
• In Vitro Model: H1395 cells; Lung; Homo sapiens (Human); CVCL_1467
• In Vitro Model: H1355 cells; Pleural effusion; Homo sapiens (Human); CVCL_1464
• In Vitro Model: Calu-6 cells; Lung; Homo sapiens (Human); CVCL_0236
• In Vitro Model: Calu-1 cells; Lung; Homo sapiens (Human); CVCL_0608
• In Vivo Model: NOD-SCID mouse PDX model; Mus musculus
• Experiment for Molecule Alteration: Immunoblotting analysis
• Experiment for Drug Resistance: Alamar blue proliferation assay

Disease- and Tissue-specific Abundances of This Molecule

ICD Disease Classification 02

Lung cancer [ICD-11: 2C25]

Differential expression of molecule in resistant diseases

• The Studied Tissue: Lung
• The Specified Disease: Lung cancer
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 1.96E-09; Fold-change: -2.13E-01; Z-score: -8.55E-01
• The Expression Level of Disease Section Compare with the Adjacent Tissue: p-value: 6.41E-06; Fold-change: -1.85E-01; Z-score: -5.43E-01

References

• Ref 1: Resistance to Durvalumab and Durvalumab plus Tremelimumab Is Associated with Functional STK11 Mutations in Patients with Non-Small Cell Lung Cancer and Is Reversed by STAT3 Knockdown .Cancer Discov. 2021 Nov;11(11):2828-2845. doi: 10.1158/2159-8290.CD-20-1543. Epub 2021 Jul 6. 10.1158/2159-8290.CD-20-1543
• Ref 2: A Transcriptional Signature Identifies LKB1 Functional Status as a Novel Determinant of MEK Sensitivity in Lung AdenocarcinomaCancer Res. 2017 Jan 1;77(1):153-163. doi: 10.1158/0008-5472.CAN-16-1639. Epub 2016 Nov 7.