Targeting anti-apoptotic pathways eliminates senescent melanocytes and leads to nevi regression

Jaskaren Kohli, Chen Ge, Eleni Fitsiou, Miriam Doepner, Simone M. Brandenburg, William J. Faller, Todd W. Ridky and Marco Demaria ()
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Jaskaren Kohli: University Medical Center Groningen
Chen Ge: University Medical Center Groningen
Eleni Fitsiou: University Medical Center Groningen
Miriam Doepner: University of Pennsylvania
Simone M. Brandenburg: University Medical Center Groningen
William J. Faller: Netherlands Cancer Institute
Todd W. Ridky: University of Pennsylvania
Marco Demaria: University Medical Center Groningen

Nature Communications, 2022, vol. 13, issue 1, 1-12

Abstract: Abstract Human melanocytic nevi (moles) result from a brief period of clonal expansion of melanocytes. As a cellular defensive mechanism against oncogene-induced hyperplasia, nevus-resident melanocytes enter a senescent state of stable cell cycle arrest. Senescent melanocytes can persist for months in mice and years in humans with a risk to escape the senescent state and progress to melanoma. The mechanisms providing prolonged survival of senescent melanocytes remain poorly understood. Here, we show that senescent melanocytes in culture and in nevi express high level of the anti-apoptotic BCL-2 family member BCL-W but remain insensitive to the pan-BCL-2 inhibitor ABT-263. We demonstrate that resistance to ABT-263 is driven by mTOR-mediated enhanced translation of another anti-apoptotic member, MCL-1. Strikingly, the combination of ABT-263 and MCL-1 inhibitors results in synthetic lethality to senescent melanocytes, and its topical application sufficient to eliminate nevi in male mice. These data highlight the important role of redundant anti-apoptotic mechanisms for the survival advantage of senescent melanocytes, and the proof-of-concept for a non-invasive combination therapy for nevi removal.

Date: 2022
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DOI: 10.1038/s41467-022-35657-9

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