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BIOMARKER:

KEAP1 mutation

i
Other names: KEAP1, Kelch Like ECH Associated Protein 1, Cytosolic Inhibitor Of Nrf2, Kelch-Like Family Member 19, Kelch-Like Protein 19, KLHL19, INrf2, KEAP1 Delta C, KIAA0132, INRF2
Entrez ID:
Related biomarkers:
2d
CRL3Keap1 E3 ligase facilitates ubiquitin-mediated degradation of oncogenic SRX to suppress colorectal cancer progression. (PubMed, Nat Commun)
Clinical sample analysis reveals that Keap1 is downregulated while SRX is overexpressed in CRC, which correlates with poor prognosis. Our findings elucidate a mechanism by which CRL3Keap1 ubiquitin ligase degrades SRX to suppress CRC progression, indicating that the Keap1-SRX axis will guide the targeted therapy towards CRC.
Journal
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MMP9 (Matrix metallopeptidase 9)
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KEAP1 mutation
8d
The Impact of Genetic Mutations on the Efficacy of Immunotherapies in Lung Cancer. (PubMed, Int J Mol Sci)
This review provides an overview of the mechanisms of FDA-approved immunotherapeutic drugs, offering an updated perspective on the current state and future developments in lung cancer therapy. More importantly, the factors that positively and negatively impact the immunotherapy's efficacy will also be discussed.
Review • Journal • IO biomarker
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EGFR (Epidermal growth factor receptor) • HER-2 (Human epidermal growth factor receptor 2) • KRAS (KRAS proto-oncogene GTPase) • BRAF (B-raf proto-oncogene) • ALK (Anaplastic lymphoma kinase) • TP53 (Tumor protein P53) • RB1 (RB Transcriptional Corepressor 1) • NF1 (Neurofibromin 1) • KEAP1 (Kelch Like ECH Associated Protein 1)
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TP53 mutation • KRAS mutation • EGFR mutation • BRAF mutation • ATM mutation • NF1 mutation • KEAP1 mutation
19d
Effective treatment strategies and key factors influencing therapeutic efficacy in advanced SMARCA4-deficient non-small cell lung cancer. (PubMed, Lung Cancer)
The addition of ICIs to local treatment shows promising results for locally advanced patients with SD-NSCLC, and first-line ICIs are associated with improved survival in metastatic SD-NSCLC. STK11/KEAP1 mutations may be linked to reduced efficacy of immunotherapy.
Journal • Tumor mutational burden • PD(L)-1 Biomarker • IO biomarker • Metastases
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PD-L1 (Programmed death ligand 1) • TMB (Tumor Mutational Burden) • STK11 (Serine/threonine kinase 11) • KEAP1 (Kelch Like ECH Associated Protein 1) • SMARCA4 (SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily A, member 4)
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PD-L1 expression • STK11 mutation • KEAP1 mutation
21d
Benchmark of screening markers for KEAP1/NFE2L2 mutations and joint analysis with the K1N2-score. (PubMed, NPJ Precis Oncol)
We tested if the RNA expression data of six pathway-related genes and NQO1-IHC might be a reliable alternative using 348 KEAP1/NFE2L2 mutation-enriched NSCLC. While TXNRD1 RNA testing was the best-performing single-gene test, the combination of single-gene screening and validation with the K1N2-score achieved the highest performance when predicting mutation status or pathway activation.
Journal
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KEAP1 (Kelch Like ECH Associated Protein 1) • NFE2L2 (Nuclear Factor, Erythroid 2 Like 2) • NQO1 (NAD(P)H dehydrogenase, quinone 1)
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KEAP1 mutation • NFE2L2 mutation
30d
Petunidin attenuates vinclozolin instigated testicular toxicity in albino rats via regulating TLR4/MyD88/TRAF6 and Nrf-2/Keap-1 pathway: A pharmacodynamic and molecular simulation approach. (PubMed, Int Immunopharmacol)
Lastly, molecular docking (MD) was performed to assess the effectiveness of PDN as a curative compound by analyzing its binding affinity with the targeted proteins (Keap1, TLR4 and StAR). Our in-silico evaluations confirmed that PDN possesses the potential to interact with binding pockets of these proteins, emphasizing its capability as a curative compound to mitigate VZN-prompted reproductive damage.
PK/PD data • Preclinical • Journal • IO biomarker
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MYD88 (MYD88 Innate Immune Signal Transduction Adaptor) • KEAP1 (Kelch Like ECH Associated Protein 1) • IL6 (Interleukin 6) • TNFA (Tumor Necrosis Factor-Alpha) • HMOX1 (Heme Oxygenase 1) • BAX (BCL2-associated X protein) • CASP3 (Caspase 3) • TLR4 (Toll Like Receptor 4) • IL1B (Interleukin 1, beta) • CAT (Catalase) • TRAF6 (TNF Receptor Associated Factor 6)
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KEAP1 mutation • BCL2 expression • BAX expression
1m
ML385, an Nrf2 Inhibitor, Synergically Enhanced Celastrol Triggered Endoplasmic Reticulum Stress in Lung Cancer Cells. (PubMed, ACS Omega)
In this study, we discovered that celastrol stimulates an abnormal rise in the reactive oxygen species (ROS) level in lung cancer cells and that the ROS scavenger N-acetylcysteine (NAC) could counteract the cell death caused by celastrol...Above all, our study found that ML385 enhanced celastrol-induced increases in ROS and ER stress, leading to lung cancer cell death. This research provides a potential strategy for the preclinical investigation of celastrol.
Journal
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KEAP1 (Kelch Like ECH Associated Protein 1) • ATF4 (Activating Transcription Factor 4)
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KEAP1 mutation
1m
Targeting NQO1 induces ferroptosis and triggers anti-tumor immunity in immunotherapy-resistant KEAP1-deficient cancers. (PubMed, Drug Resist Updat)
We validated these findings in several preclinical tumor models. Overall, KEAP1 mutations define a unique disease phenotype, and targeting its key downstream molecule NQO1 offers new hope for patients with resistance to immunotherapy.
Journal • IO biomarker
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KEAP1 (Kelch Like ECH Associated Protein 1) • NQO1 (NAD(P)H dehydrogenase, quinone 1)
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KEAP1 mutation
1m
The efficacy of immunotherapy in non-small cell lung cancer with KRAS mutation: a systematic review and meta-analysis. (PubMed, Cancer Cell Int)
The KRAS mutation and KRAS G12C mutation confer benefits that impact OS and PFS in NSCLC patients treated with immunotherapy. However, the KRAS G12D mutation negatively impacts OS compared to the KRAS non-G12D mutation. Furthermore, KRAS co-mutations involving STK11 and KEAP1/NFE2L2 are associated with a negative impact on the efficacy of immunotherapy in NSCLC patients.
Retrospective data • Review • Journal • IO biomarker
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KRAS (KRAS proto-oncogene GTPase) • STK11 (Serine/threonine kinase 11) • KEAP1 (Kelch Like ECH Associated Protein 1) • NFE2L2 (Nuclear Factor, Erythroid 2 Like 2)
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KRAS mutation • KRAS G12C • KRAS G12D • STK11 mutation • KRAS wild-type • KEAP1 mutation • RAS wild-type • KRAS G12 • NFE2L2 mutation
1m
Concurrent EGFR mutation and SMARCA4 deficiency in non-small cell lung cancer: A case report and literature review. (PubMed, Medicine (Baltimore))
This case underscores the transient efficacy of targeted therapy in SMARCA4-deficient NSCLC with concurrent EGFR mutations. It highlights the need for continuous therapeutic adjustments and emphasizes the importance of further research into effective strategies for treating this complex and challenging subset of NSCLC, as current modalities have limitations in sustained efficacy.
Review • Journal
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EGFR (Epidermal growth factor receptor) • KRAS (KRAS proto-oncogene GTPase) • ALK (Anaplastic lymphoma kinase) • TP53 (Tumor protein P53) • STK11 (Serine/threonine kinase 11) • KEAP1 (Kelch Like ECH Associated Protein 1) • LRP1B (LDL Receptor Related Protein 1B) • SMARCA4 (SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily A, member 4)
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TP53 mutation • KRAS mutation • EGFR mutation • EGFR L858R • STK11 mutation • KEAP1 mutation • SMARCA4 mutation • EGFR L858R + EGFR exon 21 deletion
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Tagrisso (osimertinib) • Focus V (anlotinib)
1m
SOS1 Inhibition Enhances the Efficacy of KRASG12C Inhibitors and Delays Resistance in Lung Adenocarcinoma. (PubMed, Cancer Res)
Here, we identified targeting proximal receptor tyrosine kinase (RTK) signaling using the SOS1 inhibitor (SOS1i) BI-3406 as a strategy to improve responses to G12Ci treatment...Treatment with SOS1i both delayed acquired G12Ci resistance and limited the total number of resistant colonies regardless of KEAP1 and STK11 mutational status. Together, these data suggest that targeting SOS1 could be an effective strategy to both enhance G12Ci efficacy and prevent G12Ci resistance regardless of co-mutations.
Journal
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KRAS (KRAS proto-oncogene GTPase) • STK11 (Serine/threonine kinase 11) • KEAP1 (Kelch Like ECH Associated Protein 1)
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STK11 mutation • KEAP1 mutation • STK11 mutation + KEAP1 mutation • STK11 deletion
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BI-3406
2ms
Trial completion date • Combination therapy • Metastases
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EGFR (Epidermal growth factor receptor) • KRAS (KRAS proto-oncogene GTPase) • ALK (Anaplastic lymphoma kinase) • STK11 (Serine/threonine kinase 11) • KEAP1 (Kelch Like ECH Associated Protein 1)
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KRAS mutation • EGFR mutation • STK11 mutation • ALK fusion • KEAP1 mutation
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Keytruda (pembrolizumab) • cisplatin • carboplatin • Imfinzi (durvalumab) • Imjudo (tremelimumab) • pemetrexed
2ms
Trial completion date • Combination therapy • Metastases
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EGFR (Epidermal growth factor receptor) • KRAS (KRAS proto-oncogene GTPase) • ALK (Anaplastic lymphoma kinase) • STK11 (Serine/threonine kinase 11) • KEAP1 (Kelch Like ECH Associated Protein 1)
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KRAS mutation • EGFR mutation • STK11 mutation • ALK fusion • KEAP1 mutation
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Keytruda (pembrolizumab) • cisplatin • carboplatin • Imfinzi (durvalumab) • Imjudo (tremelimumab) • pemetrexed
2ms
Durvalumab (D) ± Tremelimumab (T) + Chemotherapy (CT) in the First-Line Treatment of Metastatic (m) NSCLC: 5-Year Survival Data (OS) Update of the POSEIDON Study (DGHO 2024)
Updated analyses from POSEIDON after median FU of >5 y showed durable long-term OS benefit with the approved regimen of T+D+CT (vs CT alone). These results support its use as a 1L treatment option for pts with mNSCLC, including harder-to-treat subgroups such as those with PD-L1 TC <1%.
Clinical • PD(L)-1 Biomarker • IO biomarker • Metastases
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EGFR (Epidermal growth factor receptor) • PD-L1 (Programmed death ligand 1) • KRAS (KRAS proto-oncogene GTPase) • ALK (Anaplastic lymphoma kinase) • STK11 (Serine/threonine kinase 11) • KEAP1 (Kelch Like ECH Associated Protein 1)
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PD-L1 expression • KRAS mutation • EGFR wild-type • STK11 mutation • ALK wild-type • KEAP1 mutation
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VENTANA PD-L1 (SP263) Assay
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Imfinzi (durvalumab) • Imjudo (tremelimumab)
2ms
A Phase II Study of Sotorasib (AMG 510) in Participants with Previously Treated Stage IV or Recurrent KRASG12C Mutated Non-Squamous Non-Small Cell Lung Cancer (ECOG-ACRIN Lung-MAP Sub-Study) (SWOG-Fall 2024)
Ten additional participants have experienced Grade 4 treatment-related adverse events, nine of which are non-hematologic toxicities. There is one participant with a Grade 3 treatment-related Hepatobil disorders-Other due to autoimmune hepatitis.
P2 data • IO biomarker • Metastases
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EGFR (Epidermal growth factor receptor) • KRAS (KRAS proto-oncogene GTPase) • ALK (Anaplastic lymphoma kinase) • TP53 (Tumor protein P53) • ROS1 (Proto-Oncogene Tyrosine-Protein Kinase ROS) • STK11 (Serine/threonine kinase 11) • KEAP1 (Kelch Like ECH Associated Protein 1) • NFE2L2 (Nuclear Factor, Erythroid 2 Like 2) • CYP3A4 (Cytochrome P450, family 3, subfamily A, polypeptide 4)
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TP53 mutation • BRAF V600E • KRAS mutation • EGFR mutation • KRAS G12C • BRAF V600 • EGFR T790M • TP53 wild-type • STK11 mutation • ALK fusion • KEAP1 mutation • ROS1 fusion • KRAS G12 • STK11 mutation + TP53 mutation
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FoundationOne® CDx
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Lumakras (sotorasib)
2ms
Nodule-specific NRF2-targeted upregulation in patients with KEAP1 mutations and familial nontoxic multinodular goiter. (PubMed, J Clin Endocrinol Metab)
KEAP1 germline heterozygous mutations exert excessive NRF2 activity in the thyroid gland and may confer cytoprotective effects even under abundant reactive oxygen species associated with thyroid hormone production, resulting in thyroid hyperplasia with scarce degradation.
Journal
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KEAP1 (Kelch Like ECH Associated Protein 1) • GPX2 (Glutathione peroxidase 2 (gastrointestinal))
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KEAP1 mutation
2ms
Quercetin as a therapeutic agent activate the Nrf2/Keap1 pathway to alleviate lung ischemia-reperfusion injury. (PubMed, Sci Rep)
Quercetin showed preventive effects by reducing these markers, acting through modulation of the Nrf2/Keap1 pathway and inhibiting the NF-κB pathway. This anti-inflammatory effect, complementary to the antioxidant effects of quercetin, provides a multifaceted approach to cell protection that is important for developing therapeutic strategies against ischemia-reperfusion injury and could be helpful in preventive strategies against ischemia-reperfusion.
Journal • IO biomarker
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BCL2 (B-cell CLL/lymphoma 2) • TNFA (Tumor Necrosis Factor-Alpha) • HMOX1 (Heme Oxygenase 1) • BAX (BCL2-associated X protein) • IL1B (Interleukin 1, beta)
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KEAP1 mutation • HMOX1 expression
2ms
USP13 facilitates a ferroptosis-to-autophagy switch by activation of the NFE2L2/NRF2-SQSTM1/p62-KEAP1 axis dependent on the KRAS signaling pathway. (PubMed, Autophagy)
Additionally, USP13 depletion promotesan autophagy-to-ferroptosis switch invitro andin xenograft tumor mouse models, through the activation of theNFE2L2-SQSTM1/p62 (sequestosome 1)-KEAP1 axis in KRAS mutant cellsand tumor tissues. Hence, targeting USP13 effectively switchedautophagy-to-ferroptosis, thereby inhibiting KRAS (KRASproto-oncogene, GTPase) mutant LUAD, suggesting the therapeuticpromise of combining autophagy and ferroptosis in the KRAS-mutantLUAD.
Journal
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KRAS (KRAS proto-oncogene GTPase) • KEAP1 (Kelch Like ECH Associated Protein 1) • SQSTM1 (Sequestosome 1) • USP1 (Ubiquitin Specific Peptidase 1) • USP13 (Ubiquitin Specific Peptidase 13)
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KRAS mutation • KEAP1 mutation • NFE2L2 expression • NFE2L2 overexpression
2ms
Specific cancer types and prognosis in patients with variations in the KEAP1-NRF2 system: A retrospective cohort study. (PubMed, Cancer Sci)
Our results indicate that genetic alteration of the KEAP1-NRF2 pathway is a major factor in patient prognosis for each cancer type and its genetic variant. Variants in NRF2 and KEAP1 genes can characterize the biological basis of each cancer type and are involved in carcinogenesis, resistance to therapy, and other biological differences.
Retrospective data • Journal
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KEAP1 (Kelch Like ECH Associated Protein 1) • NFE2L2 (Nuclear Factor, Erythroid 2 Like 2)
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KEAP1 mutation • NFE2L2 mutation
2ms
SMARCA4 mutations and expression in lung adenocarcinoma: prognostic significance and impact on the immunotherapy response. (PubMed, FEBS Open Bio)
Additionally, immunotherapy efficacy in patients with SMARCA4 mutations depended on the co-mutant genes. Thus, SMARCA4 could be an important factor to be considered for LUAD diagnosis and treatment.
Journal • Tumor mutational burden • MSi-H Biomarker • IO biomarker
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KRAS (KRAS proto-oncogene GTPase) • TP53 (Tumor protein P53) • TMB (Tumor Mutational Burden) • MSI (Microsatellite instability) • STK11 (Serine/threonine kinase 11) • KEAP1 (Kelch Like ECH Associated Protein 1) • SMARCA4 (SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily A, member 4)
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TP53 mutation • TMB-H • MSI-H/dMMR • STK11 mutation • KEAP1 mutation • SMARCA4 mutation
2ms
KEAP1-NRF2 pathway as a novel therapeutic target for EGFR-mutant non-small cell lung cancer. (PubMed, Tuberc Respir Dis (Seoul))
We identified that NRF2 inhibition enhanced cell death and inhibited tumor growth in TKI-resistant lung cancer with EGFR-mutation. Thus, NRF2 modulation may be a novel therapeutic strategy to overcome the resistance to EGFR-tyrosine kinase inhibitors.
Journal • IO biomarker
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EGFR (Epidermal growth factor receptor) • KEAP1 (Kelch Like ECH Associated Protein 1) • NFE2L2 (Nuclear Factor, Erythroid 2 Like 2)
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EGFR mutation • EGFR expression • KEAP1 mutation • NFE2L2 mutation
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Tagrisso (osimertinib) • gefitinib
2ms
Reno-protective potential of sudachitin to mitigate paraquat instigated renal toxicity via regulating Nrf2/Keap1 pathway: An inflammatory, apoptotic and histopathological assessment. (PubMed, Chem Biodivers)
Besides, PQ exposure prompted various histopathological damages in renal tissues. Nonetheless, SCN substantially restored aforementioned alterations in renal tissues owing to its anti-oxidative, anti-inflammatory and anti-apoptotic potential.
Journal • IO biomarker
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BCL2 (B-cell CLL/lymphoma 2) • KEAP1 (Kelch Like ECH Associated Protein 1) • IL6 (Interleukin 6) • NFKB1 (Nuclear factor of kappa light polypeptide gene enhancer in B-cells 1) • BAX (BCL2-associated X protein) • CASP3 (Caspase 3) • KIM1 (Kidney injury molecule 1) • IL1B (Interleukin 1, beta) • CAT (Catalase)
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KEAP1 mutation • BCL2 expression • BAX expression • KEAP1 expression
3ms
Trial completion date • Combination therapy • Metastases
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EGFR (Epidermal growth factor receptor) • KRAS (KRAS proto-oncogene GTPase) • ALK (Anaplastic lymphoma kinase) • STK11 (Serine/threonine kinase 11) • KEAP1 (Kelch Like ECH Associated Protein 1)
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KRAS mutation • EGFR mutation • STK11 mutation • ALK fusion • KEAP1 mutation
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Keytruda (pembrolizumab) • cisplatin • carboplatin • Imfinzi (durvalumab) • Imjudo (tremelimumab) • pemetrexed
3ms
Study of MGY825 in Patients With Advanced Non-small Cell Lung Cancer (clinicaltrials.gov)
P1, N=140, Recruiting, Novartis Pharmaceuticals | Trial completion date: Aug 2026 --> Jul 2027 | Trial primary completion date: Aug 2026 --> Jul 2027
Trial completion date • Trial primary completion date • Metastases
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KEAP1 (Kelch Like ECH Associated Protein 1) • NFE2L2 (Nuclear Factor, Erythroid 2 Like 2)
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KEAP1 mutation • NFE2L2 mutation
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MGY825
3ms
Ameliorative role of catechin to combat against lindane instigated liver toxicity via modulating PI3K/PIP3/Akt, Nrf-2/Keap-1, NF-κB pathway and histological profile. (PubMed, Pestic Biochem Physiol)
LDN instigated various histological impairments in hepatic tissues. Nonetheless, concurrent administration of CTN remarkably ameliorated liver impairments via regulating aforementioned disruptions owing to its antioxidant, anti-apoptotic and histo-protective potentials.
Journal • IO biomarker
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KEAP1 (Kelch Like ECH Associated Protein 1) • AKT1 (V-akt murine thymoma viral oncogene homolog 1) • IL6 (Interleukin 6) • TNFA (Tumor Necrosis Factor-Alpha) • HMOX1 (Heme Oxygenase 1) • BAX (BCL2-associated X protein) • CASP3 (Caspase 3) • IL1B (Interleukin 1, beta) • CAT (Catalase)
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KEAP1 mutation • BCL2 expression • BAX expression • HMOX1 expression
3ms
Radiogenomics models for predicting prognosis in locally advanced non-small cell lung cancer patients undergoing definitive chemoradiotherapy. (PubMed, Transl Lung Cancer Res)
The C-index of radiomics model, genomics model and radiogenomics model all performed well in the training group (0.590 vs. 0.606 vs. 0.663) and the validation group (0.599 vs. 0.594 vs. 0.650). The radiomics model, genomics model and radiogenomics model can all predict the prognosis of dCRT for LA-NSCLC, and the radiogenomics model is superior to the single type model.
Journal • Metastases
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MET (MET proto-oncogene, receptor tyrosine kinase) • KEAP1 (Kelch Like ECH Associated Protein 1)
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KEAP1 mutation • MET mutation
3ms
KEAP1-mutant atypical meningioma: illustrative case. (PubMed, J Neurosurg Case Lessons)
To the authors' knowledge, this is the first report of KEAP1-mutant meningioma, including its clinical course after comprehensive management. Notably, treatment included multimodal radiotherapy with IMRT followed by SRS. SRS led to an excellent treatment response at the 7-month follow-up. However, radiation necrosis developed after both radiotherapy treatments, suggesting that radiological modification can be beneficial in patients with KEAP1 mutations. https://thejns.org/doi/10.3171/CASE24387.
Journal
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KEAP1 (Kelch Like ECH Associated Protein 1)
|
KEAP1 mutation
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Avastin (bevacizumab)
3ms
Durvalumab With or Without Tremelimumab in Combination With Chemotherapy in First-Line Metastatic NSCLC: Five-Year Overall Survival Outcomes from the Phase 3 POSEIDON Trial. (PubMed, J Thorac Oncol)
After median follow-up of >5 years, T+D+CT showed durable long-term OS benefit versus CT, supporting its use as first-line treatment in mNSCLC, including in patient subgroups with harder-to-treat disease.
P3 data • Journal • Combination therapy • PD(L)-1 Biomarker • IO biomarker • Metastases
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EGFR (Epidermal growth factor receptor) • PD-L1 (Programmed death ligand 1) • KRAS (KRAS proto-oncogene GTPase) • ALK (Anaplastic lymphoma kinase) • STK11 (Serine/threonine kinase 11) • KEAP1 (Kelch Like ECH Associated Protein 1)
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PD-L1 expression • KRAS mutation • EGFR wild-type • STK11 mutation • ALK wild-type • KEAP1 mutation
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Imfinzi (durvalumab) • Imjudo (tremelimumab)
3ms
Molecular profiling METex14+ non-small cell lung cancer (NSCLC): Impact of histology. (PubMed, Lung Cancer)
METex14+ alterations are a heterogeneous subgroup of NSCLC. Our analysis reveals that METex14+ nSq exhibit improved survival compared to METex14+ Sq. The distinct genomic and transcriptomic variations across histologies warrant clinical consideration.
Journal • PD(L)-1 Biomarker • BRCA Biomarker • IO biomarker
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PD-L1 (Programmed death ligand 1) • TP53 (Tumor protein P53) • TMB (Tumor Mutational Burden) • MET (MET proto-oncogene, receptor tyrosine kinase) • BRCA2 (Breast cancer 2, early onset) • STK11 (Serine/threonine kinase 11) • KEAP1 (Kelch Like ECH Associated Protein 1) • CD8 (cluster of differentiation 8) • MDM2 (E3 ubiquitin protein ligase) • CDK4 (Cyclin-dependent kinase 4) • HMGA2 (High mobility group AT-hook 2) • POT1 (Protection of telomeres 1)
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TP53 mutation • TMB-H • MET exon 14 mutation • STK11 mutation • KEAP1 mutation • POT1 mutation
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PD-L1 IHC 22C3 pharmDx • MI Tumor Seek™
4ms
Thromboembolic Events in Patients with Oncogene-Addicted Advanced NSCLC (IASLC-WCLC 2024)
TEs occurred later with EGFR and ALK , while earlier with ROS1 or KRAS with STK11, KEAP1 or SMARCA4 co-mutations compared to those with KRAS mutations alone. $$table_{7740CBC2-774F-48DA-932A-077113E7FED5}$$
Clinical • Metastases
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EGFR (Epidermal growth factor receptor) • HER-2 (Human epidermal growth factor receptor 2) • KRAS (KRAS proto-oncogene GTPase) • BRAF (B-raf proto-oncogene) • ALK (Anaplastic lymphoma kinase) • MET (MET proto-oncogene, receptor tyrosine kinase) • RET (Ret Proto-Oncogene) • ROS1 (Proto-Oncogene Tyrosine-Protein Kinase ROS) • STK11 (Serine/threonine kinase 11) • KEAP1 (Kelch Like ECH Associated Protein 1) • SMARCA4 (SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily A, member 4)
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KRAS mutation • HER-2 mutation • MET exon 14 mutation • STK11 mutation • KEAP1 mutation • ROS1 fusion • SMARCA4 mutation
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OncoPanel™ Assay
4ms
Thromboembolic Events in Patients with Oncogene-Addicted Advanced NSCLC (IASLC-WCLC 2024)
TEs occurred later with EGFR and ALK , while earlier with ROS1 or KRAS with STK11, KEAP1 or SMARCA4 co-mutations compared to those with KRAS mutations alone. Cumulative incidence of venous and arterial TEs % 0 6 weeks 6 months 1 year 2 years 3 years Overall 2.8 6 11.7 15.8 21.5 26.2 ALK 5.3 10.7 12 14.8 14.8 17 BRAF 2.1 5.8 12.9 16.3 19.5 27.9 EGFR 2 5.8 10.2 14 17.9 23 HER2 0 3.5 7.2 9.2 19.5 23 KRAS 2.7 5.1 11.3 15.3 22.5 27.1 MET 14 6.8 11.3 21.2 21.2 23.9 27.7 RET 13.3 23.3 33.3 36.6 44.5 50.1 ROS1 12 20 34.2 34.2 45.1 53.3
Clinical • Metastases
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EGFR (Epidermal growth factor receptor) • HER-2 (Human epidermal growth factor receptor 2) • KRAS (KRAS proto-oncogene GTPase) • BRAF (B-raf proto-oncogene) • ALK (Anaplastic lymphoma kinase) • MET (MET proto-oncogene, receptor tyrosine kinase) • RET (Ret Proto-Oncogene) • ROS1 (Proto-Oncogene Tyrosine-Protein Kinase ROS) • STK11 (Serine/threonine kinase 11) • KEAP1 (Kelch Like ECH Associated Protein 1) • SMARCA4 (SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily A, member 4)
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KRAS mutation • HER-2 mutation • MET exon 14 mutation • STK11 mutation • KEAP1 mutation • ROS1 fusion • SMARCA4 mutation
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OncoPanel™ Assay
5ms
Atlas of tertiary lymphoid structures in solid tumors: Genomic features and prediction of response to immunotherapy (ESMO 2024)
We assessed gene signatures indicative of B cell infiltration/TLS presence (Messina et al., 2012; Goc et al., 2014; Cabrita et al., 2020; Meylan, et al., 2022), correlating these with clinical outcomes, including overall survival (OS) and time on treatment (TOT) for ICIs such as pembrolizumab, nivolumab, and ipilimumab. This large TLS atlas based on real-world data demonstrate that TLS gene is a robust biomarker for predicting responses to immunotherapy in solid tumors.
Tumor mutational burden • PD(L)-1 Biomarker • IO biomarker
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EGFR (Epidermal growth factor receptor) • KRAS (KRAS proto-oncogene GTPase) • TMB (Tumor Mutational Burden) • MSI (Microsatellite instability) • STK11 (Serine/threonine kinase 11) • KEAP1 (Kelch Like ECH Associated Protein 1) • APC (APC Regulator Of WNT Signaling Pathway)
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KRAS mutation • EGFR mutation • STK11 mutation • KEAP1 mutation • APC mutation • TLS gene signature
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MI Tumor Seek™
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Keytruda (pembrolizumab) • Opdivo (nivolumab) • Yervoy (ipilimumab)
7ms
Arginine deprivation enriches lung cancer proteomes with cysteine by inducing arginine-to-cysteine substitutants. (PubMed, Mol Cell)
Finally, functional interrogation indicated a key role for R>C substitutants in cell survival to cisplatin, suggesting that regulatory codon reassignments endow cancer cells with more resilience to stress. Thus, we present a mechanism for enriching lung cancer proteomes with cysteines that may affect therapeutic decisions.
Journal
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ASS1 (Argininosuccinate synthase 1)
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KEAP1 mutation
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cisplatin
8ms
Redoxhigh phenotype mediated by KEAP1/STK11/SMARCA4/NRF2 mutations diminishes tissue-resident memory CD8+ T cells and attenuates the efficacy of immunotherapy in lung adenocarcinoma. (PubMed, Oncoimmunology)
The redoxhigh phenotype in LUAD is predominantly driven by mutations in KEAP1, STK11, NRF2, and SMARCA4. This phenotype diminishes the number of tissue-resident memory CD8+ T cells and attenuates the efficacy of ICIs.
Journal • IO biomarker
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EGFR (Epidermal growth factor receptor) • STK11 (Serine/threonine kinase 11) • KEAP1 (Kelch Like ECH Associated Protein 1) • CD8 (cluster of differentiation 8) • SMARCA4 (SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily A, member 4) • NFE2L2 (Nuclear Factor, Erythroid 2 Like 2)
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EGFR mutation • STK11 mutation • KEAP1 mutation • SMARCA4 mutation • NFE2L2 mutation
8ms
Differential squamous cell fates elicited by NRF2 gain of function versus KEAP1 loss of function. (PubMed, Cell Rep)
These findings demonstrate that, while cellular NRF2 levels are similarly induced, NRF2 gain of function and KEAP1 loss of function elicits distinct fates of squamous cells. The NRF2L30F mutant mouse model developed here will be instrumental in elucidating the mechanistic basis leading to NRF2-activated ESCC.
Journal
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TP53 (Tumor protein P53) • KEAP1 (Kelch Like ECH Associated Protein 1) • NFE2L2 (Nuclear Factor, Erythroid 2 Like 2)
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TP53 mutation • KEAP1 mutation • NFE2L2 mutation • TP53 expression • KEAP1 deletion
8ms
KEAP1-Mutant Lung Cancers Weaken Anti-Tumor Immunity and Promote an M2-like Macrophage Phenotype. (PubMed, Int J Mol Sci)
We show here that KEAP1-mutant cancers promote immunosuppression of the tumor microenvironment. Our data suggest KEAP1 deletion is sufficient to alter the secretion of cytokines, increase expression of immune checkpoint markers on cancer cells, and alter recruitment and differential polarization of immunosuppressive macrophages that ultimately lead to T-cell suppression.
Journal • IO biomarker
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KEAP1 (Kelch Like ECH Associated Protein 1)
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KEAP1 mutation • KEAP1 deletion
8ms
A Phase II Study of Sotorasib (AMG 510) in Participants with Previously Treated Stage IV or Recurrent KRASG12C Mutated Non-Squamous Non-Small Cell Lung Cancer (ECOG-ACRIN Lung-MAP Sub-Study) (SWOG-Spring 2024)
There have been two treatment-related deaths, one due to cardiac arrest and one due to pneumonitis. Ten additional participants have experienced Grade 4 treatment-related adverse events, nine of which are non-hematologic toxicities.
P2 data • IO biomarker • Metastases
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EGFR (Epidermal growth factor receptor) • KRAS (KRAS proto-oncogene GTPase) • ALK (Anaplastic lymphoma kinase) • TP53 (Tumor protein P53) • ROS1 (Proto-Oncogene Tyrosine-Protein Kinase ROS) • STK11 (Serine/threonine kinase 11) • KEAP1 (Kelch Like ECH Associated Protein 1) • NFE2L2 (Nuclear Factor, Erythroid 2 Like 2) • CYP3A4 (Cytochrome P450, family 3, subfamily A, polypeptide 4)
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TP53 mutation • BRAF V600E • KRAS mutation • EGFR mutation • KRAS G12C • BRAF V600 • EGFR T790M • TP53 wild-type • STK11 mutation • ALK fusion • KEAP1 mutation • ROS1 fusion • KRAS G12 • STK11 mutation + TP53 mutation
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FoundationOne® CDx
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Lumakras (sotorasib)
8ms
Glutamine antagonist DRP-104 suppresses tumor growth and enhances response to checkpoint blockade in KEAP1 mutant lung cancer. (PubMed, Sci Adv)
Using multimodal single-cell sequencing and ex vivo functional assays, we demonstrate that DRP-104 reverses T cell exhaustion, decreases Tregs, and enhances the function of CD4 and CD8 T cells, culminating in an improved response to anti-PD1 therapy. Our preclinical findings provide compelling evidence that DRP-104, currently in clinical trials, offers a promising therapeutic approach for treating patients with KEAP1 mutant lung cancer.
Journal • Checkpoint inhibition • PD(L)-1 Biomarker • IO biomarker • Checkpoint block
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KEAP1 (Kelch Like ECH Associated Protein 1) • CD8 (cluster of differentiation 8) • CD4 (CD4 Molecule)
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KEAP1 mutation
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sirpiglenastat (DRP-104)
8ms
Glutamine antagonists may KEAP lung cancer in check. (PubMed, Sci Adv)
The glutamine antagonist DRP-104 blocks purine synthesis and combines with checkpoint inhibitors to promote antitumor immunity in KEAP1/NRF2-mutant lung cancers.
Review • Journal
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KEAP1 (Kelch Like ECH Associated Protein 1) • NFE2L2 (Nuclear Factor, Erythroid 2 Like 2)
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KEAP1 mutation • NFE2L2 mutation
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sirpiglenastat (DRP-104)
8ms
AURKA emerges as a vulnerable target for KEAP1-deficient non-small cell lung cancer by activation of asparagine synthesis. (PubMed, Cell Death Dis)
Through CRISPR metabolic screens, we identified that KEAP1-knockdown cells showed the highest sensitivity to the AURKA inhibitor MLN8237...Our study unveils the pivotal role of AURKA in amino acid metabolism and identifies a specific metabolic indication for AURKA inhibitors. These findings also provide a novel clinical therapeutic target for KEAP1-mutant/deficient NSCLC, which is characterized by resistance to radiotherapy, chemotherapy, and targeted therapy.
Journal
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KEAP1 (Kelch Like ECH Associated Protein 1) • AURKA (Aurora kinase A) • ASNS (Asparagine synthetase) • ATF4 (Activating Transcription Factor 4)
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KEAP1 mutation
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alisertib (MLN8237)
9ms
Clobetasol propionate, a Nrf-2 inhibitor, sensitizes human lung cancer cells to radiation-induced killing via mitochondrial ROS-dependent ferroptosis. (PubMed, Acta Pharmacol Sin)
Interestingly, Nrf-2 overexpressing A549 cells were refractory to CP-mediated ferroptosis induction and radiosensitization. Thus, this study identified anti-psoriatic drug clobetasol propionate can be repurposed as a promising radiosensitizer for Keap-1 mutant lung cancers.
Journal
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KEAP1 (Kelch Like ECH Associated Protein 1)
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KEAP1 mutation
9ms
Molecular features of gastroenteropancreatic neuroendocrine carcinoma: A comparative analysis with lung neuroendocrine carcinoma and digestive adenocarcinomas. (PubMed, Chin J Cancer Res)
Putative targetable genes and biomarkers in GEPNEC were identified in 22.2% of the patients, and they had longer progression-free survival (PFS) upon targetable treatment &lsqb;12.5 months vs. 3.0 months, HR=0.40 (0.21-0.75), P=0.006]. This work demonstrated striking gene distinctions in GEPNEC compared with LNEC and adenocarcinoma and their clinical utility.
Journal
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KRAS (KRAS proto-oncogene GTPase) • TP53 (Tumor protein P53) • RB1 (RB Transcriptional Corepressor 1) • ARID1A (AT-rich interaction domain 1A) • KEAP1 (Kelch Like ECH Associated Protein 1) • TERT (Telomerase Reverse Transcriptase) • CTNNB1 (Catenin (cadherin-associated protein), beta 1) • CDH1 (Cadherin 1) • IL7R (Interleukin 7 Receptor)
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TP53 mutation • KRAS mutation • ARID1A mutation • KEAP1 mutation • RB1 mutation • TERT mutation • TERT amplification