HighLights
- •BRAFi resistant melanoma cells experienced significant increased level of Sestrin2, gaining protection from reactive oxidative stress (ROS)- induced cell death under BRAFi exposure.
- •The activity of mTOR signaling elevated following Sestrin2 ablation.
- •The combination of mTOR blocker and Sestrin2 knockdown generated enhanced growth suppression effects on BRAFi-resistant melanoma cells.
Abstract
Background
Treatment resistance often occurs with BRAF inhibitor (BRAFi) therapy for melanoma,
bringing in a great challenge to the treatment of melanoma patients harboring mutant
BRAF gene. Recent studies revealed redox vulnerability constitutes a novel opportunity
to overcome BRAFi resistance. Previously we found Sestrin2 provided protection to
metastatic melanoma cells by detoxifying reactive oxygen species (ROS) induced by
anoikis, but its defensive role against redox stimuli elicited by BRAFi was unclear.
Objective
In-depth explored the role of Sestrin2 in BRAFi-resistant melanoma.
Methods
Vemurafenib-resistant melanoma cells were established using 451Lu and UACC62 cell
lines carrying BRAFV600E mutation. Mechanistic studies were subsequently performed by transfection of lentiviral
vectors encoding an shRNA against SESN2 or embedded with the coding sequences of SESN2
cDNA.
Results
Elevated Sestrin2 expression was found in vemurafenib-resistance melanoma cells. Further
mechanistic studies revealed that BRAFi-resistant melanoma cells employ Sestrin2 to
adapt to higher oxidative stress under vemurafenib exposure. It was also demonstrated
that mTOR signaling was significantly activated following Sestrin2 knockdown. Given
the known promoting role of active mTOR signaling in melanoma proliferation and survival,
the effects of mTOR blocker and Sestrin2 ablation on BRAFi-resistant melanoma cells
were further tested, and the combination was found to result in enhanced inhibition
of melanoma cell growth.
Conclusions
Our findings demonstrated the contribution of Sestrin2 to the development of BRAFi
resistance and the fact that the combination of mTOR blocker assisted Sestrein2 ablation
in eliminating BRAFi resistance of melanoma. Therefore, mTOR and Sestrin2 may be novel
combinatorial therapeutic targets to overcome BRAFi resistance of melanoma.
Keywords
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Article info
Publication history
Accepted:
December 20,
2022
Received in revised form:
December 14,
2022
Received:
July 6,
2022
Publication stage
In Press Journal Pre-ProofIdentification
Copyright
© 2022 Published by Elsevier B.V. on behalf of Japanese Society for Investigative Dermatology.
