Inflammasome Sensor NLRP1 Confers Acquired Drug Resistance to Temozolomide in Human Melanoma

SIMPLE SUMMARY: Acquired drug resistance remains a challenge in the management of cancer patients. Strategies to overcome drug resistance and enhance the response include the combination therapy with agents that target known resistance mechanisms. Inflammasomes are mediators of inflammation. We previously reported the involvement of NACHT, LRR and PYD domains-containing protein (NLRP) 1/3 inflammasomes in the melanoma microenvironment and tumor growth. The aim of this study was to further determine the role of NLRP1 in acquired drug resistance in melanoma. We, for the first time, demonstrate that NLRP1 inflammasome is involved in the development of acquired drug resistance of melanoma. Because drug-tolerant cancer cells become cross-tolerant to other classes of cancer drugs, shared mechanisms could be involved in acquired drug resistance to other drugs. ABSTRACT: Cancer cells gain drug resistance through a complex mechanism, in which nuclear factor-κB (NF-κB) and interleukin-1β (IL-1β) are critical contributors. Because NACHT, LRR and PYD domains-containing protein (NLRP) inflammasomes mediate IL-1β maturation and NF-κB activation, we investigated the role of inflammasome sensor NLRP1 in acquired drug resistance to temozolomide (TMZ) in melanoma. The sensitivity of melanoma cells to TMZ was negatively correlated with the expression levels of O(6)-methylguanine-DNA methyltransferase (MGMT), the enzyme to repair TMZ-induced DNA lesions. When MGMT-low human melanoma cells (1205Lu and HS294T) were treated with TMZ for over two months, MGMT was upregulated, and cells became resistant. However, the resistance mechanism was independent of MGMT, and the cells that acquired TMZ resistance showed increased NLRP1 expression, NLRP inflammasome activation, IL-1β secretion, and NF-κB activity, which contributed to the acquired resistance to TMZ. Finally, blocking IL-1 receptor (IL-1R) signaling with IL-1R antagonist decreased TMZ-resistant 1205Lu tumor growth in vivo. Although inflammation has been associated with drug resistance in various cancers, our paper is the first to demonstrate the involvement of NLRP in the development of acquired drug resistance. Because drug-tolerant cancer cells become cross-tolerant to other classes of cancer drugs, NLRP1 might be a suitable therapeutic target in drug-resistant melanoma, as well as in other cancers.