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Atg7 Overcomes Senescence and Promotes Growth of Braf V600E-Driven Melanoma
Open accessAbstract
UNLABELLED: Macroautophagy (autophagy hereafter) may promote survival and growth of spontaneous tumors, including melanoma. We utilized a genetically engineered mouse model of melanoma driven by oncogenic BrafV600E and deficiency in the Pten tumor suppressor gene in melanocytes to test the functional consequences of loss of the essential autophagy gene autophagy-related-7, Atg7. Atg7 deficiency prevented melanoma development by BrafV600E and allelic Pten loss, indicating that autophagy is essential for melanomagenesis. Moreover, BrafV600E-mutant, Pten-null, Atg7-deficient melanomas displayed accumulation of autophagy substrates and growth defects, which extended animal survival. Atg7-deleted tumors showed increased oxidative stress and senescence, a known barrier to melanomagenesis. Treatment with the BRAF inhibitor dabrafenib decreased tumor growth and induced senescence that was more pronounced in tumors with Atg7 deficiency. Thus, Atg7 promotes melanoma by limiting oxidative stress and overcoming senescence, and autophagy inhibition may be of therapeutic value by augmenting the antitumor activity of BRAF inhibitors. SIGNIFICANCE: The essential autophagy gene Atg7 promotes development of BrafV600E-mutant, Pten-null melanomas by overcoming senescence, and deleting Atg7 facilitated senescence induction and antitumor activity of BRAF inhibition. This suggests that combinatorial BRAFV600E and autophagy inhibition may improve therapeutic outcomes in patients whose tumors have BRAFV600E/K mutations, an approach currently being explored in clinical trials.
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“In mice harbouring a Braf V600E mutation and Pten loss, deletion of Atg7 , another autophagy- related gene, facilitates melanoma formation by disabling senescence 46 .”
From Senescence and cancer — role and therapeutic opportunities (2022) · cites this paper as [46]
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“We reveal that the APOE variants exert cell-intrinsic effects on melanoma that impact primary tumor growth and metastatic capacity in a BrafV600E-driven GEMM, a model that has provided numerous important insights into melanoma biology (12,38–40).”
From Apolipoprotein E2 Stimulates Protein Synthesis and Promotes Melanoma Progression and Metastasis (2023) · cites this paper as [40]
In the citing paper
“Knockdown of the essential autophagy gene Atg7 in these mice leads to accumulation of defective mitochondria and ROS, increased senescence, decreased proliferation, and increased apoptosis86.”
From Mechanisms and prevention of UV‐induced melanoma (2018) · cites this paper as [86]
In the citing paper
“In models of BRAFV600E mutant melanoma with PTEN-deficiency, autophagy is required for tumorigenesis86.”
From Mechanisms and prevention of UV‐induced melanoma (2018) · cites this paper as [86]
In the citing paper
“Increased autophagy has been shown to increase cell survival in BRAFV600E mutant melanomas85–87.”
From Mechanisms and prevention of UV‐induced melanoma (2018) · cites this paper as [86]
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Citations
Cites
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Improved survival with vemurafenib in melanoma with BRAF V600E mutation
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The Unfolded Protein Response: From Stress Pathway to Homeostatic Regulation
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Autophagy and the Integrated Stress Response
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Cellular senescence: from physiology to pathology
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Combined BRAF and MEK inhibition in melanoma with BRAF V600 mutations
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Impairment of starvation-induced and constitutive autophagy in Atg7 -deficient mice
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BRAFE600-associated senescence-like cell cycle arrest of human naevi
Michaloglou, C., Vredeveld, L. C. W., Soengas, M. S., Denoyelle, C., Kuilman, T., van der Horst, C. M. A. M., Majoor, D. M., Shay, J. W., Mooi, W. J., & Peeper, D. S. (2005) · Nature · doi:10.1038/nature03890 · Cited by 2,160
Cited by
Sorted by citations
Levy, J. M. M., Towers, C. G., & Thorburn, A. (2017) · Nature Reviews Cancer · doi:10.1038/nrc.2017.53 · Cited by 2,526
Autophagy in major human diseases
Klionsky, D. J., Petroni, G., Amaravadi, R. K., Baehrecke, E. H., Ballabio, A., Boya, P., Bravo‐San Pedro, J. M., Cadwell, K., Cecconi, F., Choi, A. M. K., et al. (2021) · The EMBO Journal · doi:10.15252/embj.2021108863 · Cited by 1,585
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Self-citationTargeting Autophagy in Cancer: Recent Advances and Future Directions
Amaravadi, R. K., Kimmelman, A. C., & Debnath, J. (2019) · Cancer Discovery · doi:10.1158/2159-8290.cd-19-0292 · Cited by 928
Targeting the RAS/RAF/MAPK pathway for cancer therapy: from mechanism to clinical studies
Bahar, M. E., Kim, H. J., & Kim, D. R. (2023) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-023-01705-z · Cited by 888
Metadata
- Authors
- Xie, X., Koh, J. Y., Price, S., White, E., & Mehnert, J. M.
- Affiliations
- Rutgers, The State University of New Jersey (US)
- Corresponding author
- White, Eileen
- Mehnert, Janice M.
- Venue
- Cancer Discovery
- Published
- 2015-04-01
- Volume
- 5
- Issue
- 4
- Pages
- 410-423
- ISSN
- 2159-8274 (ISSN-L)
- 2159-8290
- PMC
- PMC4390491
- OpenAlex
- W2010656553
- Cited by
- 208
- References
- 50
- Citations by year
- 2026: 5 · 2025: 9 · 2024: 17 · 2023: 18 · 2022: 18 · 2021: 35 · 2020: 23 · 2019: 24 · 2018: 16 · 2017: 17 · 2016: 21 · 2015: 5
- FWCI
- 15.42
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Cancer Discovery (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Rutgers Cancer Institute of New Jersey
- National Cancer Institute (P30-CA72720, L30 CA136372, R01CA130893, P30CA072720, R01CA163591)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Autophagy in Disease and Therapy
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Melanoma and MAPK Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Physiology › Calcium signaling and nucleotide metabolism
- Keywords
- ATG7, autophagy, melanoma, BRAF V600E mutation, PTEN loss, cellular senescence, oxidative stress, dabrafenib, BRAF inhibitor combination therapy, melanomagenesis, autophagy inhibition
- MeSH terms
- Autophagy-Related Protein 7, Animals, Autophagy, Cell Transformation, Neoplastic, Disease Models, Animal, Heterozygote, Melanoma, Mice, Transgenic, Microtubule-Associated Proteins, Mutation, Gene Expression Regulation, Neoplastic, Cellular Senescence, Gene Deletion, Oxidative Stress, Cell Line, Tumor, Protein Kinase Inhibitors, Proto-Oncogene Proteins B-raf, Cell Proliferation, PTEN Phosphohydrolase, Mice, Gene Knockout Techniques
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