STAG2 and STAG3 Prevent BRAF Inhibitor Resistance in Melanoma

BRAF inhibitors achieve a high response rate in patients with BRAF-mutant melanoma, but the majority of patients eventually acquire drug resistance. Although several resistance mechanisms have been identified, a subset of BRAF inhibitor–resistant melanomas are driven by unknown mechanisms. To discover additional resistance mechanisms, Shen and colleagues performed whole-exome sequencing of paired pretreatment and post-relapse tumor samples from a patient with BRAF inhibitor–resistant melanoma. A loss-of-function mutation in stromal antigen 2 (STAG2), which encodes a subunit of the cohesin complex, was greatly enriched in the post-relapse sample and was significantly mutated in The Cancer Genome Atlas pan-cancer analysis, and STAG3 loss-of-function mutations were also found in post-relapse samples. Consistent with this finding, STAG2 and STAG3 expression were reduced in BRAF inhibitor–resistant melanoma cell lines and in 7 of 9 post-relapse samples from patients with melanoma treated with BRAF inhibitors alone or in combination with MEK inhibitors, suggesting that loss of STAG2/3 is involved in the development of BRAF inhibitor resistance. Depletion of STAG2 or STAG3 reduced the sensitivity of BRAF-mutant melanoma cells to BRAF inhibition in vitro and in vivo via reactivation of MAPK signaling, as evidenced by increased phospho-ERK levels. Mechanistically, depletion of STAG2 or STAG3 decreased the binding of CCCTC-binding factor (CTCF) to the promoter of the ERK phosphatase DUSP6, resulting in decreased DUSP6 expression and, consequently, enhanced ERK phosphorylation and activation. Collectively, these findings identify a previously unappreciated mechanism of resistance to BRAF inhibitors and suggest that STAG2 and STAG3 may suppress tumor growth via regulation of ERK signaling.

Shen CH, Kim SH, Trousil S, Frederick DT, Piris A, Yuan P, et al. Loss of cohesin complex components STAG2 or STAG3 confers resistance to BRAF inhibition in melanoma. Nat Med 2016;22:1056–61.

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