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Ref Type Journal Article
PMID (33071215)
Authors Binkley MS, Jeon YJ, Nesselbush M, Moding EJ, Nabet BY, Almanza D, Kunder C, Stehr H, Yoo CH, Rhee S, Xiang M, Chabon JJ, Hamilton E, Kurtz DM, Gojenola L, Owen SG, Ko RB, Shin JH, Maxim PG, Lui NS, Backhus LM, Berry MF, Shrager JB, Ramchandran KJ, Padda SK, Das M, Neal JW, Wakelee HA, Alizadeh AA, Loo BW, Diehn M
Title KEAP1/NFE2L2 Mutations Predict Lung Cancer Radiation Resistance That Can Be Targeted by Glutaminase Inhibition.
Journal Vol Issue Date Pages Journal Short Title
Cancer discovery 10 12 2020 Dec 1826-1841 Cancer Discov
URL
Abstract Text Tumor genotyping is not routinely performed in localized non-small cell lung cancer (NSCLC) due to lack of associations of mutations with outcome. Here, we analyze 232 consecutive patients with localized NSCLC and demonstrate that KEAP1 and NFE2L2 mutations are predictive of high rates of local recurrence (LR) after radiotherapy but not surgery. Half of LRs occurred in tumors with KEAP1/NFE2L2 mutations, indicating that they are major molecular drivers of clinical radioresistance. Next, we functionally evaluate KEAP1/NFE2L2 mutations in our radiotherapy cohort and demonstrate that only pathogenic mutations are associated with radioresistance. Furthermore, expression of NFE2L2 target genes does not predict LR, underscoring the utility of tumor genotyping. Finally, we show that glutaminase inhibition preferentially radiosensitizes KEAP1 -mutant cells via depletion of glutathione and increased radiation-induced DNA damage. Our findings suggest that genotyping for KEAP1/NFE2L2 mutations could facilitate treatment personalization and provide a potential strategy for overcoming radioresistance conferred by these mutations. SIGNIFICANCE: This study shows that mutations in KEAP1 and NFE2L2 predict for LR after radiotherapy but not surgery in patients with NSCLC. Approximately half of all LRs are associated with these mutations and glutaminase inhibition may allow personalized radiosensitization of KEAP1/NFE2L2 -mutant tumors. This article is highlighted in the In This Issue feature, p. 1775 .

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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
KEAP1 D173N missense no effect KEAP1 D173N does not lie within any known functional domains of the Keap1 protein (UniProt.org). D173N results in a similar decrease in Nfe2l2 target gene expression and reduction in cell survival following irradiation and hydrogen peroxide treatment to wild-type Keap1 in culture (PMID: 33071215).
KEAP1 D236V missense no effect KEAP1 D236V lies within the BACK domain of the Keap1 protein (UniProt.org). D236V results in a similar decrease in Nfe2l2 target gene expression and reduction in cell survival following irradiation and hydrogen peroxide treatment to wild-type Keap1 in culture (PMID: 33071215).
KEAP1 D78N missense no effect KEAP1 D78N lies within the BTB domain of the Keap1 protein (UniProt.org). D78N results in a similar decrease in Nfe2l2 target gene expression and reduction in cell survival following irradiation and hydrogen peroxide treatment to wild-type Keap1 in culture (PMID: 33071215).
KEAP1 G332C missense loss of function KEAP1 G332C lies within Kelch repeat 1 of the Keap1 protein (UniProt.org). G332C results in loss of Nfe2l2 inhibition leading to increased Nfe2l2 target gene and protein expression and increased cell survival following irradiation and hydrogen peroxide treatment in culture (PMID: 33071215).
KEAP1 H311R missense loss of function KEAP1 H311R does not lie within any known functional domains of the Keap1 protein (UniProt.org). H311R results in loss of Nfe2l2 inhibition leading to increased Nfe2l2 target gene and protein expression and increased cell survival following irradiation and hydrogen peroxide treatment in culture (PMID: 33071215).
KEAP1 M283fs frameshift loss of function KEAP1 M283fs results in a change in the amino acid sequence of the Keap1 protein beginning at aa 283 of 624, likely resulting in premature truncation of the functional protein (UniProt.org). M283fs results in loss of Nfe2l2 inhibition leading to increased Nfe2l2 target gene and protein expression and increased cell survival following irradiation and hydrogen peroxide treatment in culture (PMID: 33071215).
KEAP1 P455fs frameshift loss of function KEAP1 P455fs results in a change in the amino acid sequence of the Keap1 protein beginning at aa 455 of 624, likely resulting in premature truncation of the functional protein (UniProt.org). P455fs results in loss of Nfe2l2 inhibition leading to increased Nfe2l2 target gene and protein expression and increased cell survival following irradiation and hydrogen peroxide treatment in culture (PMID: 33071215).
KEAP1 R135L missense loss of function KEAP1 R135L lies within the BTB domain of the Keap1 protein (UniProt.org). R135L results in loss of Nfe2l2 inhibition leading to increased Nfe2l2 target gene and protein expression and increased cell survival following irradiation and hydrogen peroxide treatment in culture (PMID: 33071215).
KEAP1 R362W missense loss of function KEAP1 R362W lies within Kelch repeat 1 of the Keap1 protein (UniProt.org). R362W results in loss of Nfe2l2 inhibition leading to increased Nfe2l2 target gene and protein expression and increased cell survival following irradiation and hydrogen peroxide treatment in culture (PMID: 33071215).
KEAP1 V271M missense loss of function KEAP1 V271M lies within the BACK domain of the Keap1 protein (UniProt.org). V271M results in a loss of NRF2-mediated repression compared to wild-type Keap1 in an in vitro assay (PMID: 30150714), and results in loss of Nfe2l2 inhibition leading to increased Nfe2l2 target gene and protein expression and increased cell survival following irradiation and hydrogen peroxide treatment in culture (PMID: 33071215).
KEAP1 V453M missense no effect KEAP1 V453M lies within Kelch repeat 3 of the Keap1 protein (UniProt.org). V453M results in a similar decrease in Nfe2l2 target gene expression and reduction in cell survival following irradiation and hydrogen peroxide treatment to wild-type Keap1 in culture (PMID: 33071215).
KEAP1 Y490* nonsense loss of function KEAP1 Y490* results in a premature truncation of the Keap1 protein at amino acid 490 of 624 (UniProt.org). Y490* confers a loss of function to the Keap1 protein as demonstrated by loss of Nfe2l2 inhibition leading to increased Nfe2l2 target gene expression and cell survival following irradiation or hydrogen peroxide treatment in culture (PMID: 33071215).
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
KEAP1 dec exp lung non-small cell carcinoma sensitive Radiotherapy + Telaglenastat Preclinical - Cell culture Actionable In a preclinical study, Telaglenstat (CB-839) increased sensitivity of a KEAP1 knockdown non-small cell lung cancer cell line to radiotherapy in culture (PMID: 33071215). 33071215
KEAP1 loss lung adenocarcinoma sensitive Radiotherapy + Telaglenastat Preclinical - Cell culture Actionable In a preclinical study, Telaglenstat (CB-839) increased sensitivity of KEAP1 knockout non-small cell lung cancer cells to radiotherapy in culture, demonstrating increased cell death and DNA double-strand breaks (PMID: 33071215). 33071215
KEAP1 mutant lung adenocarcinoma sensitive Radiotherapy + Telaglenastat Preclinical - Cell culture Actionable In a preclinical study, Telaglenstat (CB-839) increased sensitivity of a non-small cell lung cancer cell line harboring a KEAP1 mutation to radiotherapy in culture (PMID: 33071215). 33071215
KEAP1 loss lung adenocarcinoma sensitive Buthionine sulfoximine + Radiotherapy Preclinical - Cell culture Actionable In a preclinical study, Buthionine sulfoximine (BSO) increased sensitivity of KEAP1 knockout non-small cell lung cancer cells to radiotherapy in culture (PMID: 33071215). 33071215