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Ref Type Journal Article
PMID (27821489)
Authors Kaufman JM, Yamada T, Park K, Timmers CD, Amann JM, Carbone DP
Title A Transcriptional Signature Identifies LKB1 Functional Status as a Novel Determinant of MEK Sensitivity in Lung Adenocarcinoma.
Journal Vol Issue Date Pages Journal Short Title
Cancer research 77 1 2017 Jan 01 153-163 Cancer Res
URL
Abstract Text LKB1 is a commonly mutated tumor suppressor in non-small cell lung cancer that exerts complex effects on signal transduction and transcriptional regulation. To better understand the downstream impact of loss of functional LKB1, we developed a transcriptional fingerprint assay representing this phenotype. This assay was predictive of LKB1 functional loss in cell lines and clinical specimens, even those without detected sequence alterations in the gene. In silico screening of drug sensitivity data identified putative LKB1-selective drug candidates, revealing novel associations not apparent from analysis of LKB1 mutations alone. Among the candidates, MEK inhibitors showed robust association with signature expression in both training and testing datasets independent of RAS/RAF mutations. This susceptibility phenotype is directly altered by RNA interference-mediated LKB1 knockdown or by LKB1 re-expression into mutant cell lines and is readily observed in vivo using a xenograft model. MEK sensitivity is dependent on LKB1-induced changes in AKT and FOXO3 activation, consistent with genomic and proteomic analyses of LKB1-deficient lung adenocarcinomas. Our findings implicate the MEK pathway as a potential therapeutic target for LKB1-deficient cancers and define a practical NanoString biomarker to identify functional LKB1 loss. Cancer Res; 77(1); 153-63. ©2016 AACR.

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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
STK11 W332* lung non-small cell carcinoma sensitive Trametinib Preclinical - Cell culture Actionable In a preclinical study, non-small cell lung cancer cell lines harboring STK11 inactivating mutations, such as STK11 W332*, demonstrated increased sensitivity to Mekinist (trametinib) in culture (PMID: 27821489). 27821489
STK11 inact mut Advanced Solid Tumor sensitive Trametinib Preclinical - Cell culture Actionable In a preclinical study, the presence of an STK11 loss expression signature, which correlated to STK11 inactivating mutations, was associated with increased sensitivity to Mekinist (trametinib) in human tumor cell lines in culture (PMID: 27821489). 27821489
STK11 inact mut Advanced Solid Tumor sensitive PD-0325901 Preclinical - Cell culture Actionable In a preclinical study, the presence of an STK11 loss expression signature, which correlates with STK11 inactivating mutations, was associated with increased sensitivity to PD-0325901 in human tumor cell lines in culture (PMID: 27821489). 27821489
STK11 dec exp lung non-small cell carcinoma sensitive Trametinib Preclinical - Cell line xenograft Actionable In a preclinical study, knockdown of STK11 increased sensitivity to Mekinist (trametinib) in non-small cell lung cancer cell lines in culture and in xenograft models (PMID: 27821489). 27821489
STK11 inact mut Advanced Solid Tumor sensitive CI-1040 Preclinical - Cell culture Actionable In a preclinical study, the presence an STK11 loss expression signature, which correlates with STK11 inactivating mutations, was associated with increased sensitivity to CI-1040 (PD184352) in human tumor cell lines in culture (PMID: 27821489). 27821489
STK11 Q37* lung non-small cell carcinoma sensitive Trametinib Preclinical - Cell culture Actionable In a preclinical study, non-small cell lung cancer cell lines harboring STK11 inactivating mutations, such as STK11 Q37*, demonstrated increased sensitivity to Mekinist (trametinib) in culture (PMID: 27821489). 27821489
STK11 E57fs lung non-small cell carcinoma sensitive Trametinib Preclinical - Cell culture Actionable In a preclinical study, non-small cell lung cancer cell lines harboring STK11 inactivating mutations, such as STK11 E57fs, demonstrated increased sensitivity to Mekinist (trametinib) in culture (PMID: 27821489). 27821489
STK11 inact mut Advanced Solid Tumor sensitive Refametinib Preclinical - Cell culture Actionable In a preclinical study, the presence of an STK11 loss expression signature, which correlates with STK11 inactivating mutations, was associated with increased sensitivity to Refametinib (BAY86-9766) in human tumor cell lines in culture (PMID: 27821489). 27821489
STK11 K48fs lung non-small cell carcinoma sensitive Trametinib Preclinical - Cell culture Actionable In a preclinical study, non-small cell lung cancer cell lines harboring STK11 inactivating mutations, such as STK11 K48fs, demonstrated increased sensitivity to Mekinist (trametinib) in culture (PMID: 27821489). 27821489
STK11 E199* lung non-small cell carcinoma sensitive Trametinib Preclinical - Cell culture Actionable In a preclinical study, non-small cell lung cancer cell lines harboring STK11 inactivating mutations, such as STK11 E199*, demonstrated increased sensitivity to Mekinist (trametinib) in culture (PMID: 27821489). 27821489
STK11 inact mut Advanced Solid Tumor sensitive Selumetinib Preclinical - Cell culture Actionable In a preclinical study, the presence of an STK11 inactivating mutation and STK11 loss expression signature was associated with increased sensitivity to Selumetinib (AZD6244) in human tumor cell lines in culture (PMID: 27821489). 27821489
STK11 inact mut lung non-small cell carcinoma sensitive Trametinib Preclinical - Cell culture Actionable In a preclinical study, non-small cell lung cancer cell lines harboring STK11 inactivating mutations demonstrated increased sensitivity to Mekinist (trametinib) in culture (PMID: 27821489). 27821489