Repurposing Melanoma Chemotherapy to Activate Inflammasomes in the Treatment of BRAF/MAPK Inhibitor Resistant Melanoma

Repurposing Melanoma Chemotherapy to Activate Inflammasomes in the Treatment of BRAF/MAPK Inhibitor Resistant Melanoma.

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Item Type: Article
Status: Published
Official URL:
Journal or Publication Title: Journal of Investigative Dermatology
Volume: 142
Number: 5
Page Range: 1444-1455.e10
Date: 22 October 2021
Divisions: Melanoma Epigenetics Laboratory
Melanoma Oncology and Immunology
Depositing User: General Admin
Identification Number: 10.1016/j.jid.2021.09.030
ISSN: 0022202X
Date Deposited: 26 Sep 2022 00:11

The development of resistance to treatments of melanoma is commonly associated with an upregulation of the MAPK pathway and the development of an undifferentiated state. Previous studies have suggested that melanoma with these resistance characteristics may be susceptible to innate death mechanisms such as pyroptosis triggered by the activation of inflammasomes. In this study, we have taken cell lines from patients before and after the development of resistance to BRAF V600 inhibitors and exposed the resistant melanoma to temozolomide (a commonly used chemotherapy) with and without chloroquine to inhibit autophagy. It was found that melanoma with an inflammatory undifferentiated state appeared susceptible to this combination when tested in vitro and in vivo against xenografts in nonobese diabetic scid gamma mice. Translation of the latter results into patients would promise durable responses in patients treated by the combination. The inflammasome and death mechanism involved appeared to vary between melanoma and involved either AIM2 or NLRP3 inflammasomes and gasdermin D or E. These preliminary studies have raised questions as to the selectivity for different inflammasomes in different melanoma and their selective targeting by chemotherapy. They also question whether the inflammatory state of melanoma may be used as biomarkers to select patients for inflammasome-targeted therapy.

Ahmed, Farzana
Tseng, Hsin-Yi
Ahn, Antonio
Gunatilake, Dilini
Alavi, Sara
Eccles, Michael
Rizos, Helen
Gallagher, Stuart J
Tiffen, Jessamy C
Hersey, Peter
Emran, Abdullah Al
Last Modified: 26 Sep 2022 00:11

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