STAG2/3 increase sensitivity to BRAF inhibition by reducing ERK activation in melanoma cells.
Major finding: STAG2/3 increase sensitivity to BRAF inhibition by reducing ERK activation in melanoma cells.
Mechanism: STAG2 interacts with CTCF to upregulate the ERK phosphatase DUSP6, suppressing ERK activation.
Impact: STAG2 and STAG3 suppress melanoma growth via regulation of ERK signaling.
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.
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