TP53, CDKN2A/P16, and NFE2L2/NRF2 regulate the incidence of pure- and combined-small cell lung cancer in mice

Hamad, Samera H.; Montgomery, Stephanie A.; Simon, Jeremy M.; Bowman, Brittany M.; Spainhower, Kyle B.; Murphy, Ryan M.; Knudsen, Erik S.; Fenton, Suzanne E.; Randell, Scott H.; Holt, Jeremiah; Hayes, D. Neil; Witkiewicz, Agnieszka K.; Oliver, Trudy G.; Major, Michael B.; Weissman, Bernard E.

doi:10.1038/s41388-022-02348-0

Cited by 12 publications

(13 citation statements)

References 67 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This result demonstrates a direct role for Nrf2 hyperactivation but we cannot exclude the possibility that alternative KEAP1 substrates, such as PGAM5 45 , PALB2 46 , MCM3 47 or EMSY 48 , contribute to the block in tumor progression. In agreement with our findings, a Keap1-binding defective Nrf2 E79Q mouse model of small-cell lung cancer (SCLC) with p53/ p16 inactivation 53 also displayed Nrf2 downregulation in aggressive SCLC tumors. The exact mechanism(s) by which high NRF2 activity impairs tumor cell proliferation and tumor progression remains to be determined.…”

Section: Discussionsupporting

confidence: 92%

Distinct Nrf2 Signaling Thresholds Mediate Lung Tumor Initiation and Progression

DeBlasi

Falzone

Caldwell

et al. 2022

Preprint

View full text Add to dashboard Cite

Mutations in the KEAP1-NRF2 pathway occur in up to a third of non-small cell lung cancer (NSCLC) cases and often confer resistance to therapy and poor outcomes. Here, we developed murine alleles of the KEAP1 and NRF2 mutations found in human NSCLC and comprehensively interrogated their impact on tumor initiation and progression. Chronic Nrf2 stabilization by Keap1 or Nrf2 mutation was not sufficient to induce tumorigenesis, even in the absence of tumor suppressors p53 or Lkb1. When combined with KrasG12D/+, constitutive Nrf2 activation promoted lung tumor initiation and early progression of hyperplasia to low-grade tumors but impaired their progression to advanced-grade tumors, which was reversed by Nrf2 deletion. Finally, NRF2 overexpression in KEAP1 mutant NSCLC cell lines was detrimental to cell proliferation, viability, and anchorage-independent colony formation. Collectively, our results establish the context-dependence and activity threshold for NRF2 during the lung tumorigenic process.

show abstract

Section: Discussionsupporting

confidence: 92%

Distinct Nrf2 Signaling Thresholds Mediate Lung Tumor Initiation and Progression

DeBlasi

Falzone

Caldwell

et al. 2022

Preprint

View full text Add to dashboard Cite

show abstract

“…This result demonstrates a direct role for Nrf2 hyperactivation but we cannot exclude the possibility that alternative KEAP1 substrates, such as PGAM5 ( 51 ), PALB2 ( 52 ), MCM3 ( 53 ) or EMSY ( 54 ), contribute to the block in tumor progression. In agreement with our findings, a Keap1-binding defective Nrf2 E79Q mouse model of small-cell lung cancer (SCLC) with p53/ p16 inactivation ( 60 ) also displayed Nrf2 downregulation in aggressive SCLC tumors. The exact mechanism(s) by which high NRF2 activity impairs tumor cell proliferation and tumor progression remains to be determined.…”

Section: Discussionsupporting

confidence: 91%

Distinct Nrf2 Signaling Thresholds Mediate Lung Tumor Initiation and Progression

et al. 2023

View full text Add to dashboard Cite

Mutations in the KEAP1-NRF2 pathway occur in up to a third of non-small cell lung cancer (NSCLC) cases and often confer resistance to therapy and poor outcomes. Here, we developed murine alleles of the KEAP1 and NRF2 mutations found in human NSCLC and comprehensively interrogated their impact on tumor initiation and progression. Chronic NRF2 stabilization by Keap1 or Nrf2 mutation was not sufficient to induce tumorigenesis, even in the absence of tumor suppressors p53 or LKB1. When combined with KrasG12D/+, constitutive NRF2 activation promoted lung tumor initiation and early progression of hyperplasia to low-grade tumors but impaired their progression to advanced-grade tumors, which was reversed by NRF2 deletion. 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.

show abstract

“…The complexity of the story continues since many models of NRF2-mediated malignancy require co-mutation of other oncogenic drivers and/or tumor suppressors, but different combinations yield disparate results. There was no increase in tumor incidence in small cell lung cancer initiated by inhaled Cre-adenovirus in TRP53 fl/fl ; P16 fl/fl mice when LSL-NRF2 E79Q/+ was activated, although the tumor histology subtype was altered (Hamad et al, 2022). In fact, a large subset of tumors failed to express the mutant NRF2 despite recombination, and the authors concluded that it was silenced due to a deleterious effect on tumor development.…”

Section: Transformation and Initiationmentioning

confidence: 98%

The Multi-Faceted Consequences of NRF2 Activation throughout Carcinogenesis

Occhiuto

Moerland

Leal

et al. 2023

Molecules and Cells

View full text Add to dashboard Cite

The oxidative balance of a cell is maintained by the Kelch-like ECH-associated protein 1 (KEAP1)/nuclear factor erythroid 2-related factor 2 (NRF2) pathway. This cytoprotective pathway detoxifies reactive oxygen species and xenobiotics. The role of the KEAP1/NRF2 pathway as pro-tumorigenic or anti-tumorigenic throughout stages of carcinogenesis (including initiation, promotion, progression, and metastasis) is complex. This mini review focuses on key studies describing how the KEAP1/NRF2 pathway affects cancer at different phases. The data compiled suggest that the roles of KEAP1/NRF2 in cancer are highly dependent on context; specifically, the model used (carcinogen-induced vs genetic), the tumor type, and the stage of cancer. Moreover, emerging data suggests that KEAP1/NRF2 is also important for regulating the tumor microenvironment and how its effects are amplified either by epigenetics or in response to co-occurring mutations. Further elucidation of the complexity of this pathway is needed in order to develop novel pharmacological tools and drugs to improve patient outcomes.

show abstract

TP53, CDKN2A/P16, and NFE2L2/NRF2 regulate the incidence of pure- and combined-small cell lung cancer in mice

Cited by 12 publications

References 67 publications

Distinct Nrf2 Signaling Thresholds Mediate Lung Tumor Initiation and Progression

Distinct Nrf2 Signaling Thresholds Mediate Lung Tumor Initiation and Progression

Distinct Nrf2 Signaling Thresholds Mediate Lung Tumor Initiation and Progression

The Multi-Faceted Consequences of NRF2 Activation throughout Carcinogenesis

Contact Info

Product

Resources

About