News - NFE2L2 mutation

Association between Locoregional Failure and NFE2L2/KEAP1/CUL3 Mutations in NRG/RTOG 9512: A Randomized Trial of Radiation Fractionation in T2N0 Glottic Cancer. (PubMed, Clin Cancer Res)

NFE2L2/KEAP1/CUL3 mutations may predict radiation treatment failure in T2N0 glottic cancer.

3 days ago

Journal

KEAP1 (Kelch Like ECH Associated Protein 1) • NFE2L2 (Nuclear Factor, Erythroid 2 Like 2)

KEAP1 mutation • NFE2L2 mutation

24d

Development of mutated β-catenin gene signature to identify CTNNB1 mutations from whole and spatial transcriptomic data in patients with HCC. (PubMed, JHEP Rep)

Additionally, a higher MBGS expression score was associated with lack of significant improvement in overall survival or progression-free survival in the atezolizumab-bevacizumab arm vs. the sorafenib arm in the IMbrave150 cohort. We have developed a molecular signature that could serve as a companion diagnostic and uses bulk or spatial transcriptomic data to identify a unique subclass of liver tumors. This subgroup of liver cancer patients derive limited benefit from the current standard of care and are expected to benefit from specialized directed therapies that are on the horizon.

24 days ago

Journal • Gene Signature • IO Companion diagnostic • PD(L)-1 Biomarker • IO biomarker • PD(L)-1 companion diagnostic

CTNNB1 (Catenin (cadherin-associated protein), beta 1)

MET mutation • CTNNB1 mutation • NFE2L2 mutation

Avastin (bevacizumab) • Tecentriq (atezolizumab) • sorafenib

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.

1 month ago

Journal

KEAP1 (Kelch Like ECH Associated Protein 1) • NFE2L2 (Nuclear Factor, Erythroid 2 Like 2) • NQO1 (NAD(P)H dehydrogenase, quinone 1)

KEAP1 mutation • NFE2L2 mutation

2ms

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.

2 months ago

Retrospective data • Review • Journal • IO biomarker

KRAS (KRAS proto-oncogene GTPase) • STK11 (Serine/threonine kinase 11) • KEAP1 (Kelch Like ECH Associated Protein 1) • NFE2L2 (Nuclear Factor, Erythroid 2 Like 2)

KRAS mutation • KRAS G12C • KRAS G12D • STK11 mutation • KRAS wild-type • KEAP1 mutation • RAS wild-type • KRAS G12 • NFE2L2 mutation

3ms

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.

3 months ago

Retrospective data • Journal

KEAP1 (Kelch Like ECH Associated Protein 1) • NFE2L2 (Nuclear Factor, Erythroid 2 Like 2)

KEAP1 mutation • NFE2L2 mutation

3ms

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.

3 months ago

Journal • IO biomarker

EGFR (Epidermal growth factor receptor) • KEAP1 (Kelch Like ECH Associated Protein 1) • NFE2L2 (Nuclear Factor, Erythroid 2 Like 2)

EGFR mutation • EGFR expression • KEAP1 mutation • NFE2L2 mutation

Tagrisso (osimertinib) • gefitinib

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

3 months ago

Trial completion date • Trial primary completion date • Metastases

KEAP1 (Kelch Like ECH Associated Protein 1) • NFE2L2 (Nuclear Factor, Erythroid 2 Like 2)

KEAP1 mutation • NFE2L2 mutation

MGY825

8ms

Prevalence and Associations of Co-occurrence of NFE2L2 Mutations and Chromosome 3q26 Amplification in Lung Cancer. (PubMed, Glob Med Genet)

Conclusions NFE2L2 mutations display notable heterogeneity in lung cancer. The coexistence of NFE2L2 mutations and 3q26 amplification warrants in-depth exploration of their potential clinical implications and treatment approaches for affected patients.

8 months ago

Journal

TP53 (Tumor protein P53) • PIK3CA (Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha) • CDKN2A (Cyclin Dependent Kinase Inhibitor 2A) • LRP1B (LDL Receptor Related Protein 1B) • NFE2L2 (Nuclear Factor, Erythroid 2 Like 2) • SOX2 • KMT2B (Lysine Methyltransferase 2B) • IRF2 (Interferon Regulatory Factor 2) • ZMAT3 (Zinc Finger Matrin-Type 3)

PIK3CA mutation • NFE2L2 mutation

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.

8 months ago

Journal • IO biomarker

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)

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.

8 months ago

Journal

TP53 (Tumor protein P53) • KEAP1 (Kelch Like ECH Associated Protein 1) • NFE2L2 (Nuclear Factor, Erythroid 2 Like 2)

TP53 mutation • KEAP1 mutation • NFE2L2 mutation • TP53 expression • KEAP1 deletion

9ms

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.

9 months ago

Review • Journal

KEAP1 (Kelch Like ECH Associated Protein 1) • NFE2L2 (Nuclear Factor, Erythroid 2 Like 2)

KEAP1 mutation • NFE2L2 mutation

sirpiglenastat (DRP-104)

10ms

Clinicopathological and molecular characteristics of esophageal carcinoma with ductal differentiation: analysis of 17 cases (PubMed, Zhonghua Bing Li Xue Za Zhi)

At the signaling pathway level, the mutation frequency of NOTCH signaling pathway (P=0.041) was significantly higher, while the mutation frequencies of NRF2 pathway (P=0.013) and PI3K pathway (P=0.009) were significantly lower than that of esophageal squamous cell carcinoma. Esophageal carcinoma with ductal differentiation is a type of esophageal carcinoma with unique morphology, and its molecular changes are also significantly different from those of conventional esophageal squamous cell carcinoma.

10 months ago

Journal

TP63 (Tumor protein 63) • CDKN1C (Cyclin Dependent Kinase Inhibitor 1C)

NFE2L2 mutation

10ms

Impact of KEAP1/STK11 co-mutations and NRF2 signaling on resistance to adagrasib in advanced NSCLC (AACR 2024)

Background: KRAS G12C inhibitors (G12Ci) are revolutionizing the therapeutic landscape of advanced NSCLC, but mechanisms of limited clinical efficacy observed in some patients (pts) merit continued exploration. Co-mutations in KEAP1 and STK11 and NRF2 signaling define a subgroup of KG12C NSCLC pts with markedly distinct outcomes upon treatment with ada. The mTORi and ada combination shows high efficacy for targeting KG12C NSCLC harboring KEAP1 and STK11 co-mutations. The clinical safety and efficacy of mTORi nab-sirolimus and ada will be determined in the ongoing KRYSTAL-19 trial (NCT05840510).

10 months ago

Metastases

KRAS (KRAS proto-oncogene GTPase) • STK11 (Serine/threonine kinase 11) • KEAP1 (Kelch Like ECH Associated Protein 1)

KRAS mutation • STK11 mutation • KEAP1 mutation • NFE2L2 mutation • KEAP1 expression

HTG Transcriptome Panel

Krazati (adagrasib) • Fyarro (nanoparticle albumin-bound rapamycin)

10ms

ARID1A loss is associated with increased NRF2 signaling in human head and neck squamous cell carcinomas. (PubMed, PLoS One)

Overall, our results support a context-dependent functional link between SWI/SNF and NRF2 mutations across human cancers and implicate ARID1A inactivation in HPV-negative HNSC in promoting tumor progression and survival through activation of the KEAP1-NRF2 signaling pathway. The tumor-specific effects of these mutations open a new area of study for how mutations in the KEAP1-NRF2 pathway and the SWI/SNF complex contribute to cancer.

10 months ago

Journal

ARID1A (AT-rich interaction domain 1A) • NFE2L2 (Nuclear Factor, Erythroid 2 Like 2)

ARID1A mutation • KEAP1 mutation • NFE2L2 mutation

10ms

PET/CT-Based Radiogenomics Supports KEAP1/NFE2L2 Pathway Targeting for Non-Small Cell Lung Cancer Treated with Curative Radiotherapy. (PubMed, J Nucl Med)

The same radiomics model was validated on the volumetric modulated arc radiotherapy cohort as patients were significantly stratified on the basis of their risk of LR with a hazard ratio of 2.61 (P = 0.02). Our approach enables the prediction of MutKEAP1/NFE2L2 using PET/CT-extracted radiomics features and efficiently classifies patients at risk of LR in an external cohort treated with radiotherapy.

10 months ago

Journal

KEAP1 (Kelch Like ECH Associated Protein 1) • NFE2L2 (Nuclear Factor, Erythroid 2 Like 2)

KEAP1 mutation • NFE2L2 mutation

11ms

NRF2 mutation enhances the immune escape of hepatocellular carcinoma by reducing STING activation. (PubMed, Biochem Biophys Res Commun)

Our study also revealed that NRF2 mutation greatly reduced the effect of STING activating based immunotherapy. It is important to simultaneously inhibit the activity of NRF2 when using STING agonist for the treatment of HCC patients carrying NRF2 mutation.

11 months ago

Journal • IO biomarker

KEAP1 (Kelch Like ECH Associated Protein 1) • NFE2L2 (Nuclear Factor, Erythroid 2 Like 2) • STING (stimulator of interferon response cGAMP interactor 1)

NFE2L2 mutation • STING expression

11ms

Genome-wide analyses reveal the contribution of somatic variants to the immune landscape of multiple cancer types. (PubMed, PLoS Genet)

By integrating multiple RNA-seq data, a NRF2 gene signature was curated, which predicts anti-PD1 therapy response better than CD274 gene alone in a mixed cohort of different subtypes of non-small cell lung cancer (NSCLC) including LUAD, highlighting the important role of KEAP1-NRF2 axis in shaping the TME in NSCLC. Finally, a list of overexpressed ligands in NRF2 pathway activated cancer cells were identified and could potentially be targeted for TME remodeling in LUAD.

11 months ago

Journal • PD(L)-1 Biomarker • IO biomarker

PD-L1 (Programmed death ligand 1) • KEAP1 (Kelch Like ECH Associated Protein 1) • NFE2L2 (Nuclear Factor, Erythroid 2 Like 2)

PD-L1 expression • PD-L1 overexpression • KEAP1 mutation • NFE2L2 mutation

11ms

Prognostic and predictive biomarkers in paediatric solid tumours. (PubMed, Pathology)

The prognosis of rhabdomyosarcoma, for example, primarily depends on histological and molecular characteristics. Advances in our understanding of clinically significant biomarkers will translate into more precise diagnoses, improved risk stratification and more effective and less toxic treatment in this challenging group of patients.

11 months ago

Review • Journal

TP53 (Tumor protein P53) • TERT (Telomerase Reverse Transcriptase) • MYCN (MYCN Proto-Oncogene BHLH Transcription Factor) • CTNNB1 (Catenin (cadherin-associated protein), beta 1) • NFE2L2 (Nuclear Factor, Erythroid 2 Like 2)

TP53 mutation • MYCN amplification • CTNNB1 mutation • NFE2L2 mutation • TERT mutation • TERT promoter mutation

11ms

Nrf2, A Target for Precision Oncology in Cancer Prognosis and Treatment. (PubMed, J Cancer Prev)

Hence understanding mutations in Nrf2 would have a significant impact on the prognosis and treatment of cancer in the era of precision medicine. This perspective would provide an insight into the genetic alterations in Nrf2 and suggest the application of small molecules, RNAi, and genome editing technologies, particularly CRISR-Cas9, in therapeutic intervention of cancer in the context of the involvement of Nrf2 mutations.

11 months ago

Review • Journal

NFE2L2 (Nuclear Factor, Erythroid 2 Like 2)

NFE2L2 mutation

1year

Evaluation of a real-world clinico-genomics database of patients with upper gastrointestinal (GI) malignancies in Japan. (ASCO-GI 2024)

As part of a nationwide cancer genome screening project, J-SCRUM GI SCREEN database provides comprehensive genomic information for Asian population (Japan). The prevalence of key actionable gene alterations in each tumor type was highly comparable between J-SCRUM GI-SCREEN and TCGA data.

1 year ago

Clinical • Real-world evidence • BRCA Biomarker • Genomic data • Real-world

HER-2 (Human epidermal growth factor receptor 2) • KRAS (KRAS proto-oncogene GTPase) • TP53 (Tumor protein P53) • PIK3CA (Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha) • MET (MET proto-oncogene, receptor tyrosine kinase) • BRCA1 (Breast cancer 1, early onset) • BRCA2 (Breast cancer 2, early onset) • MYC (V-myc avian myelocytomatosis viral oncogene homolog) • CDKN2A (Cyclin Dependent Kinase Inhibitor 2A) • NFE2L2 (Nuclear Factor, Erythroid 2 Like 2)

TP53 mutation • KRAS mutation • BRCA2 mutation • BRCA1 mutation • HER-2 amplification • PIK3CA mutation • MET amplification • KRAS G12D • ATM mutation • KRAS G12V • MYC amplification • CDKN2A mutation • ATM deletion • KRAS G12 • NFE2L2 mutation • KRAS deletion

1year

Prognostic Significance and Clinical Correlations of Myeloid Mutations in Myelofibrosis Based on Their Functional Class (ASH 2023)

Current analysis revealed distinctive clinical characteristics and survival outcomes associated with specific categories of mutated myeloid genes in pts with PMF, largely overlapping with the ICC defined "myelodysplasia-related gene mutations" category.

1 year ago

Clinical

KRAS (KRAS proto-oncogene GTPase) • TP53 (Tumor protein P53) • NRAS (Neuroblastoma RAS viral oncogene homolog) • IDH1 (Isocitrate dehydrogenase (NADP(+)) 1) • IDH2 (Isocitrate Dehydrogenase (NADP(+)) 2) • DNMT3A (DNA methyltransferase 1) • NF1 (Neurofibromin 1) • JAK2 (Janus kinase 2) • RUNX1 (RUNX Family Transcription Factor 1) • SF3B1 (Splicing Factor 3b Subunit 1) • ASXL1 (ASXL Transcriptional Regulator 1) • TET2 (Tet Methylcytosine Dioxygenase 2) • PTPN11 (Protein Tyrosine Phosphatase Non-Receptor Type 11) • SRSF2 (Serine and arginine rich splicing factor 2) • U2AF1 (U2 Small Nuclear RNA Auxiliary Factor 1) • SETBP1 (SET Binding Protein 1) • CALR (Calreticulin) • SH2B3 (SH2B Adaptor Protein 3) • ZRSR2 (Zinc Finger CCCH-Type, RNA Binding Motif And Serine/Arginine Rich 2)

TP53 mutation • SRSF2 mutation • U2AF1 mutation • NFE2L2 mutation • CALR mutation

1year

Immunoediting of KEAP1-NRF2 mutant tumours is required to circumvent NRF2-mediated immune surveillance. (PubMed, Redox Biol)

This immunoediting takes the form of reduced antigen presentation by the MHC-I complex, coupled with reduced expression of activating ligands for NK cells. Together, these modifications to the immunogenicity of NRF2-activated cancers inhibit immune effector cell infiltration and engagement, and contribute to the formation of the immunologically cold tumour microenvironment which is a characteristic feature of NRF2-activated cancers.

1 year ago

Journal • IO biomarker

KEAP1 (Kelch Like ECH Associated Protein 1) • NFE2L2 (Nuclear Factor, Erythroid 2 Like 2)

KEAP1 mutation • NFE2L2 mutation

1year

KEAP1/NRF2 Mutations in Stem Cells Define an Aggressive Subset of Head and Neck Cancer Patients Who Have a Poor Prognosis, Lung Metastasis, and Therapeutic Failure. (PubMed, Cancers (Basel))

These associations were partly driven by HN-CSCs, in which Keap1/Nrf2 mutations were overrepresented in fast progressors and associated with an increased risk of disease progression. Our findings suggest that molecular genotyping of HN-CSCs may facilitate personalized treatment strategies and assist in identifying patients who are likely to benefit from chemotherapy.

1 year ago

Journal

KEAP1 (Kelch Like ECH Associated Protein 1) • NFE2L2 (Nuclear Factor, Erythroid 2 Like 2)

KEAP1 mutation • NFE2L2 mutation

1year

Disentangling the Joint and Distinct Immunomodulation and Vulnerability Between KEAP1/NFE2L2 and SMARCA4 Alterations in Lung Adenocarcinoma (ESMO-IO 2023)

KEAP1/NFE2L2-MUT tumors showed various immunological abnormalities, highlighting the need for identifying targets to reinvigorate the immune response. SMARCA4-MUT tumors may be vulnerable to complement-targeted therapy.

1 year ago

IO biomarker • Immunomodulating

EGFR (Epidermal growth factor receptor) • KEAP1 (Kelch Like ECH Associated Protein 1) • SMARCA4 (SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily A, member 4) • NFE2L2 (Nuclear Factor, Erythroid 2 Like 2) • AKR1C1 (Aldo-Keto Reductase Family 1 Member C1) • AKR1C2 (Aldo-Keto Reductase Family 1 Member C2)

EGFR mutation • KEAP1 mutation • SMARCA4 mutation • NFE2L2 mutation

1year

IACS-6274 With or Without Bevacizumab and Paclitaxel for the Treatment of Advanced Solid Tumors (clinicaltrials.gov)

P1, N=54, Recruiting, M.D. Anderson Cancer Center | N=84 --> 54

1 year ago

Enrollment change • Metastases

PD-L1 (Programmed death ligand 1) • PIK3CA (Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha) • PTEN (Phosphatase and tensin homolog) • STK11 (Serine/threonine kinase 11) • ARID1A (AT-rich interaction domain 1A) • NF1 (Neurofibromin 1) • KEAP1 (Kelch Like ECH Associated Protein 1) • PD-1 (Programmed cell death 1) • NFE2L2 (Nuclear Factor, Erythroid 2 Like 2)

PIK3CA mutation • PTEN mutation • ARID1A mutation • STK11 mutation • NF1 mutation • KEAP1 mutation • NFE2L2 mutation • PIK3CA mutation + PTEN mutation

Avastin (bevacizumab) • paclitaxel • Truqap (capivasertib) • IPN60090

1year

DYNAMIC EVOLUTION OF CIRCULATING TUMOR DNA IN PATIENTS WITH HEPATOCELLULAR CARCINOMA ACROSS TUMOR STAGES AND TREATMENTS (AASLD 2023)

Finally, a total of 179 plasmas in 50 patients with unresectable HCC treated by atezolizumab/bevacizumab were analyzed. Circulating tumor DNA offers dynamic information about tumor biology representing a non-invasive tool potentially useful to guide HCC clinical management.

1 year ago

Clinical • PD(L)-1 Biomarker • Circulating tumor DNA

TP53 (Tumor protein P53) • PIK3CA (Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha) • ARID1A (AT-rich interaction domain 1A) • TERT (Telomerase Reverse Transcriptase) • CTNNB1 (Catenin (cadherin-associated protein), beta 1) • NFE2L2 (Nuclear Factor, Erythroid 2 Like 2) • AFP (Alpha-fetoprotein) • ARID2 (AT-Rich Interaction Domain 2)

TP53 mutation • PIK3CA mutation • ATM mutation • NFE2L2 mutation • TERT mutation

Avastin (bevacizumab) • Tecentriq (atezolizumab)

1year

Pan-cancer analysis of NFE2L2 mutations identifies a subset of lung cancers with distinct genomic and improved immunotherapy outcomes. (PubMed, Cancer Cell Int)

Our study found that patients with Nrf2-activating mutation had improved immunotherapy outcomes than patients with wild type in NSCLC and other tumor cohorts, implying that Nrf2-activating mutation defined a distinct subset of pan-cancers and might have implications as a biomarker for guiding ICI treatment, especially NSCLC.

1 year ago

Journal • Tumor mutational burden • IO biomarker • Pan tumor

TMB (Tumor Mutational Burden) • NFE2L2 (Nuclear Factor, Erythroid 2 Like 2)

TMB-H • KEAP1 mutation • NFE2L2 mutation

1year

Testing of the Anti Cancer Drugs CB-839 HCl (Telaglenastat) and MLN0128 (Sapanisertib) in Advanced Stage Non-small Cell Lung Cancer (clinicaltrials.gov)

P1; Trial completion date: Sep 2023 --> Sep 2024 | Trial primary completion date: Sep 2023 --> Sep 2024

1 year ago

Trial completion date • Trial primary completion date • Metastases

KRAS (KRAS proto-oncogene GTPase) • BRAF (B-raf proto-oncogene) • ALK (Anaplastic lymphoma kinase) • ROS1 (Proto-Oncogene Tyrosine-Protein Kinase ROS) • KEAP1 (Kelch Like ECH Associated Protein 1) • NFE2L2 (Nuclear Factor, Erythroid 2 Like 2)

BRAF V600E • KRAS mutation • EGFR mutation • BRAF V600 • BRAF V600K • KEAP1 mutation • NFE2L2 mutation

Guardant360® CDx • MSK-IMPACT

sapanisertib (CB-228) • telaglenastat (CB-839)

1year

PET-Based Radiogenomics Supports KEAP1/NFE2L2 Pathway Targeting for Non-Small Cell Lung Cancer Treated with Curative Radiotherapy. (PubMed, Int J Radiat Oncol Biol Phys)

Our three-step approach enables the prediction of the Mut using PET/CT-extracted radiomics features and efficiently classified patient at risk of LR relapse in an external cohort treated with radiotherapy. This first evidence should be further evaluated on larger cohorts, and implemented in LR risk prediction models.

1 year ago

Journal

KEAP1 (Kelch Like ECH Associated Protein 1) • NFE2L2 (Nuclear Factor, Erythroid 2 Like 2)

KEAP1 mutation • NFE2L2 mutation

over1year

Comprehensive analyses of the clinicopathological features and genomic mutations of combined hepatocellular-cholangiocarcinoma. (PubMed, Hepatol Res)

The study suggested that there were two subtypes of cHCC-CCA, one involving TP53 mutations in the early stage of the carcinogenic process and the other not involving such mutations. The comparison of the variants between primary and recurrent tumors suggested that cHCC-CCA was derived from an identical clone.

over 1 year ago

Journal

TP53 (Tumor protein P53) • IDH1 (Isocitrate dehydrogenase (NADP(+)) 1) • IDH2 (Isocitrate Dehydrogenase (NADP(+)) 2) • BAP1 (BRCA1 Associated Protein 1) • NFE2L2 (Nuclear Factor, Erythroid 2 Like 2)

TP53 mutation • NFE2L2 mutation

over1year

Testing Whether Cancers With Specific Mutations Respond Better to Glutaminase Inhibitor, Telaglenastat Hydrochloride, Anti-Cancer Treatment, BeGIN Study (clinicaltrials.gov)

P2, N=108, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Aug 2023 --> Aug 2024 | Trial primary completion date: Aug 2023 --> Aug 2024

over 1 year ago

Trial completion date • Trial primary completion date • Pan tumor

STK11 (Serine/threonine kinase 11) • NF1 (Neurofibromin 1) • KEAP1 (Kelch Like ECH Associated Protein 1) • NFE2L2 (Nuclear Factor, Erythroid 2 Like 2)

STK11 mutation • NF1 mutation • KEAP1 mutation • NFE2L2 mutation

telaglenastat (CB-839)

over1year

Study of MGY825 in Patients With Advanced Non-small Cell Lung Cancer (clinicaltrials.gov)

P1, N=140, Recruiting, Novartis Pharmaceuticals | Active, not recruiting --> Recruiting

over 1 year ago

Enrollment open • Metastases

KEAP1 (Kelch Like ECH Associated Protein 1) • NFE2L2 (Nuclear Factor, Erythroid 2 Like 2)

KEAP1 mutation • NFE2L2 mutation

MGY825

over1year

Biological insights in non-small cell lung cancer. (PubMed, Cancer Biol Med)

Consequently, gasdermin E is activated, thus leading to permeabilization of the cytoplasmic membrane and cell-lytic pyroptosis (indicated by characteristic cell membrane ballooning). Breakthroughs in KRAS G12C allele-specific inhibitors and potential mechanisms of resistance are also discussed herein.

over 1 year ago

Review • Journal • IO biomarker

EGFR (Epidermal growth factor receptor) • KRAS (KRAS proto-oncogene GTPase) • ALK (Anaplastic lymphoma kinase) • KEAP1 (Kelch Like ECH Associated Protein 1) • CD8 (cluster of differentiation 8) • NFE2L2 (Nuclear Factor, Erythroid 2 Like 2) • CASP3 (Caspase 3) • GPX4 (Glutathione Peroxidase 4) • SLC7A11 (Solute Carrier Family 7 Member 11) • GSDME (Gasdermin E)

TP53 mutation • KRAS G12C • KEAP1 mutation • NFE2L2 mutation

over1year

KEAP1/NFE2L2 pathway signature outperforms KEAP1/NFE2L2 mutation status and reveals alternative pathway-activating mutations in Non-Small Cell Lung Cancer. (PubMed, J Thorac Oncol)

The K1N2-score identified KEAP1/NFE2L2-activated NSCLC by robustly detecting KEAP1/NFE2L2mut cases and discovering alternative genomic activators. It is a potential means for selecting patients with a constitutively active KEAP1/NFE2L2 pathway.

over 1 year ago

Journal

SMARCA4 (SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily A, member 4) • NFE2L2 (Nuclear Factor, Erythroid 2 Like 2)

KEAP1 mutation • SMARCA4 mutation • NFE2L2 mutation

over1year

Roles of NRF2 in DNA damage repair. (PubMed, Cell Oncol (Dordr))

NRF2 participates in a variety of DNA repair pathways and plays important roles in maintaining genome stability. NRF2 is a potential target for cancer treatment.

over 1 year ago

Review • Journal

NFE2L2 (Nuclear Factor, Erythroid 2 Like 2)

NFE2L2 mutation • NFE2L2 expression

over1year

Distinct Nrf2 Signaling Thresholds Mediate Lung Tumor Initiation and Progression. (PubMed, Cancer Res)

Finally, NRF2 overexpression in KEAP1 mutant human NSCLC cell lines was detrimental to cell proliferation, viability, and anchorage-independent colony formation. Collectively, these results establish the context-dependence and activity threshold for NRF2 during the lung tumorigenic process.

over 1 year ago

Journal

KRAS (KRAS proto-oncogene GTPase) • STK11 (Serine/threonine kinase 11) • NFE2L2 (Nuclear Factor, Erythroid 2 Like 2)

TP53 mutation • KRAS G12D • KEAP1 mutation • KRAS G12 • NFE2L2 mutation • KEAP1 expression

over1year

Study of MGY825 in Patients With Advanced Non-small Cell Lung Cancer (clinicaltrials.gov)

P1, N=1, Active, not recruiting, Novartis Pharmaceuticals | Trial completion date: Feb 2025 --> Aug 2026 | Trial primary completion date: Feb 2025 --> Aug 2026

over 1 year ago

Trial completion date • Trial primary completion date • Metastases

KEAP1 (Kelch Like ECH Associated Protein 1) • NFE2L2 (Nuclear Factor, Erythroid 2 Like 2)

KEAP1 mutation • NFE2L2 mutation

MGY825

over1year

Black tea bioactive phytoconstituents realign NRF2 for anticancer activity in lung adenocarcinoma. (PubMed, Front Pharmacol)

A non-responsive LUAD cell line, A549, was the best sensitized towards cisplatin upon pre-treatment with BT...BT-mediated regulation of NRF2-KEAP1 and their upstream networks (EGFR/RAS/RAF/ERK) sufficed as a better anticancer agent than synthetic NRF2 modulators. Therefore, BT may be indicated as a potent multi-modal small molecule for increasing drug responsiveness in LUAD cells by maintaining NRF2/KEAP1 axis at an optimum level.

over 1 year ago

Journal

EGFR (Epidermal growth factor receptor) • KEAP1 (Kelch Like ECH Associated Protein 1) • MMP9 (Matrix metallopeptidase 9)

NFE2L2 mutation

cisplatin

over1year

Study to Investigate DRP-104 in Adults With Advanced Solid Tumors (clinicaltrials.gov)

P2a, N=61, Terminated, Dracen Pharmaceuticals, Inc. | N=246 --> 61 | Trial completion date: Dec 2023 --> Mar 2023 | Active, not recruiting --> Terminated; Company decision to closing study and discontinue further patient enrollment.

over 1 year ago

Enrollment change • Trial completion date • Trial termination • Metastases

STK11 (Serine/threonine kinase 11) • KEAP1 (Kelch Like ECH Associated Protein 1) • NFE2L2 (Nuclear Factor, Erythroid 2 Like 2)

STK11 mutation • KEAP1 mutation • NFE2L2 mutation

Tecentriq (atezolizumab) • sirpiglenastat (DRP-104)

over1year

Molecular characterization of nectin-4 in non-small cell lung cancer subtypes. (ASCO 2023)

As enfortumab vedotin, an antibody-drug conjugate directed against nectin-4, has been FDA approved for advanced urothelial carcinoma, this holds treatment implications...NFE2L2 alterations in SQ and STK11, KEAP1 mutations in AD, which are associated with poor immunotherapy (IO) response, were enriched in Q4 tumors. This suggests that the immune landscape associated with high nectin-4 expression in NSCLC may be driven by the dysregulated KEAP1-NFE2L2 pathway. Targeted therapy towards nectin-4 may benefit these NSCLC subtypes that do not respond well to IO.

over 1 year ago

PD(L)-1 Biomarker • IO biomarker

HER-2 (Human epidermal growth factor receptor 2) • PD-L1 (Programmed death ligand 1) • STK11 (Serine/threonine kinase 11) • CD8 (cluster of differentiation 8) • NFE2L2 (Nuclear Factor, Erythroid 2 Like 2) • HAVCR2 (Hepatitis A Virus Cellular Receptor 2) • IDO1 (Indoleamine 2,3-dioxygenase 1) • NECTIN4 (Nectin Cell Adhesion Molecule 4) • CD80 (CD80 Molecule) • CD86 (CD86 Molecule)

PD-L1 expression • HER-2 mutation • STK11 mutation • KEAP1 mutation • NFE2L2 mutation • NECTIN4 expression

PD-L1 IHC 22C3 pharmDx • MI Tumor Seek™

Padcev (enfortumab vedotin-ejfv)