Targeting NFE2L2/KEAP1 Mutations in Advanced NSCLC With the TORC1/2 Inhibitor TAK-228

Paik, Paul K.; Fan, Pang-Dian; Qeriqi, Besnik; Namakydoust, Azadeh; Daly, Bobby; Ahn, Linda S.; Kim, Rachel; Plodkowski, Andrew J.; Ni, Ai; Chang, Jason C.; Fanaroff, Rachel; Ladanyi, Marc; Stanchina, Elisa de; Rudin, Charles M.

doi:10.1016/j.jtho.2022.09.225

Cited by 13 publications

(5 citation statements)

References 28 publications

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“…In this study, the mTORC1 signaling pathway was significantly activated in the NFE2L2 mutated patients with NSCLC, implying that TORC1 inhibitors were likely to exhibit considerable therapeutic efficacy in NFE2L2 mutated NSCLC patients. This finding appeared to be consistent with findings from a trial study in which TAK-228, a TORC1/2 inhibitor, demonstrated superior therapy efficacy in NFE2L2-mutated LUSC compared to KEAP1-mutated LUSC, KRAS/NFE2L2- or KEAP1-mutated NSCLC, despite the fact that the majority of patients received platinum-based chemotherapy and immunotherapy [ 73 ]. Thus, the NFE2L2 mutation can assist in classifying and identifying ICI patients, may have major implications for precision-targeted applications.…”

Section: Discussionsupporting

confidence: 87%

Pan-cancer analysis of NFE2L2 mutations identifies a subset of lung cancers with distinct genomic and improved immunotherapy outcomes

Wang,

Li,

Xuan

et al. 2023

Cancer Cell Int

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Background Mutations in the KEAP1-NFE2L2 signaling pathway were linked to increased tumorigenesis and aggressiveness. Interestingly, not all hotspot mutations on NFE2L2 were damaging; some even were activating. However, there was conflicting evidence about the association between NFE2L2 mutation and Nrf2-activating mutation and responsiveness to immune checkpoint inhibitors (ICIs) in non-small cell lung cancer (NSCLC) and other multiple cancers. Methods The study with the largest sample size (n = 49,533) explored the landscape of NFE2L2 mutations and their impact response/resistance to ICIs using public cohorts. In addition, the in-house WXPH cohort was used to validate the efficacy of immunotherapy in the NFE2L2 mutated patients with NSCLC. Results In two pan-cancer cohorts, Nrf2-activating mutation was associated with higher TMB value compared to wild-type. We identified a significant association between Nrf2-activating mutation and shorter overall survival in pan-cancer patients and NSCLC patients but not in those undergoing ICIs treatment. Similar findings were obtained in cancer patients carrying the NFE2L2 mutation. Furthermore, in NSCLC and other cancer cohorts, patients with NFE2L2 mutation demonstrated more objective responses to ICIs than patients with wild type. Our in-house WXPH cohort further confirmed the efficacy of immunotherapy in the NFE2L2 mutated patients with NSCLC. Lastly, decreased inflammatory signaling pathways and immune-depleted immunological microenvironments were enriched in Nrf2-activating mutation patients with NSCLC. Conclusions 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.

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Section: Discussionsupporting

confidence: 87%

Pan-cancer analysis of NFE2L2 mutations identifies a subset of lung cancers with distinct genomic and improved immunotherapy outcomes

Wang,

Li,

Xuan

et al. 2023

Cancer Cell Int

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“…Telaglenastat (CB-839) is a glutaminase inhibitor that has anti-tumor activity in KEAP1/NRF2-mutated NSCLC cell lines and xenograft models [104]. Sapanisertib, a mTOR inhibitor, was shown to have selective antitumor activity in NRF2-activating NSCLC in an in vivo xenograft model [105]. Therefore, the combination of telaglenastat and sapanisertib was hypothesized to have synergistic efficacy in treating NRF2/KEAP1-altered NSCLC [106].…”

Section: Nrf2mentioning

confidence: 99%

Emerging Targeted Therapies in Advanced Non-Small-Cell Lung Cancer

Correia

Wang

et al. 2023

Cancers

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Lung cancer remains the leading cause of cancer-related mortality worldwide. Non-small-cell lung cancer (NSCLC) is the most common type and is still incurable for most patients at the advanced stage. Targeted therapy is an effective treatment that has significantly improved survival in NSCLC patients with actionable mutations. However, therapy resistance occurs widely among patients leading to disease progression. In addition, many oncogenic driver mutations in NSCLC still lack targeted agents. New drugs are being developed and tested in clinical trials to overcome these challenges. This review aims to summarize emerging targeted therapy that have been conducted or initiated through first-in-human clinical trials in the past year.

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“…KEAP1 and STK11 mutations are negative prognostic factors in NSCLC [30]. Novel agents like mTORC 1/2 inhibitors (Sapanisertib) alone or in combination with Telaglenastat (glutaminase inhibitor) are being studied in KEAP1/STK11 mutant NSCLC (NCT03872427; NCT04250545) [31].…”

Section: Discussionmentioning

confidence: 99%

The Clinical, Genomic, and Transcriptomic Landscape of BRAF Mutant Cancers

Kazandjian,

Rousselle,

Dankner

et al. 2024

Cancers

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Background: BRAF mutations are classified into four molecularly distinct groups, and Class 1 (V600) mutant tumors are treated with targeted therapies. Effective treatment has not been established for Class 2/3 or BRAF Fusions. We investigated whether BRAF mutation class differed according to clinical, genomic, and transcriptomic variables in cancer patients. Methods: Using the AACR GENIE (v.12) cancer database, the distribution of BRAF mutation class in adult cancer patients was analyzed according to sex, age, primary race, and tumor type. Genomic alteration data and transcriptomic analysis was performed using The Cancer Genome Atlas. Results: BRAF mutations were identified in 9515 (6.2%) samples among 153,834, with melanoma (31%), CRC (20.7%), and NSCLC (13.9%) being the most frequent cancer types. Class 1 harbored co-mutations outside of the MAPK pathway (TERT, RFN43) vs. Class 2/3 mutations (RAS, NF1). Across all tumor types, Class 2/3 were enriched for alterations in genes involved in UV response and WNT/β-catenin. Pathway analysis revealed enrichment of WNT/β-catenin and Hedgehog signaling in non-V600 mutated CRC. Males had a higher proportion of Class 3 mutations vs. females (17.4% vs. 12.3% q = 0.003). Non-V600 mutations were generally more common in older patients (aged 60+) vs. younger (38% vs. 15% p < 0.0001), except in CRC (15% vs. 30% q = 0.0001). Black race was associated with non-V600 BRAF alterations (OR: 1.58; p < 0.0001). Conclusions: Class 2/3 BRAFs are more present in Black male patients with co-mutations outside of the MAPK pathway, likely requiring additional oncogenic input for tumorigenesis. Improving access to NGS and trial enrollment will help the development of targeted therapies for non-V600 BRAF mutations.

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Targeting NFE2L2/KEAP1 Mutations in Advanced NSCLC With the TORC1/2 Inhibitor TAK-228

Cited by 13 publications

References 28 publications

Pan-cancer analysis of NFE2L2 mutations identifies a subset of lung cancers with distinct genomic and improved immunotherapy outcomes

Pan-cancer analysis of NFE2L2 mutations identifies a subset of lung cancers with distinct genomic and improved immunotherapy outcomes

Emerging Targeted Therapies in Advanced Non-Small-Cell Lung Cancer

The Clinical, Genomic, and Transcriptomic Landscape of BRAF Mutant Cancers

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