What Causes Treatment Resistance in Melanoma?

The inactivation of mutations in STAG2 or STAG3 was found to be the genetic mechanism of BRAF inhibitor resistance among patients with melanoma, and can cause the reactivation of the cell-growth signaling pathway.

There are several known mechanisms behind the development of treatment resistance. This includes mutations in other genes in the MAPK pathway, which avoids the suppression of BRAF activity. However, as many as 25% of resistance to BRAF inhibitors cases do not involve the identified mechanisms.

In a study published by Nature Medicine, researchers used human tumor samples that were taken before treatment and after the development of resistance to BRAF inhibitor vemurafinib to conduct whole-exome sequencing. After comparing novel mutations from the post-resistance sample to a list of known cancer-associated mutations, researchers found a single significant mutation in the tumor suppressor STAG2.

Although the genes STAG1 and STAG3 code for subunits of the cohesin complex, they may also play a role in the regulation of gene expression. Several cohesin complex genes are known to be mutated in other types of cancer, this included STAG2.

Researchers examined the levels of all 3 STAG proteins in a panel of treatment-resistance melanoma cell lines, identifying reduced expression of STAG 2 and STAG3 in several lines. This included some that were resistant to BRAF and the protein MEK.

Scientists were able to identify what may be the responsible STAG2 mutation, and were also able to identify STAG3 mutations in pretreatment samples of tumors that quickly development resistance to treatment. Experiments were conducted on cultured melanoma cell lines, and in tumors that had been implanted in mice.

The results of the study showed that inactivating the expression of STAG2 and STAG3 reduced the sensitivity to BRAF inhibition by reactivating a later stage of the MAPK pathway. When either type of protein expression increased in BRAF-mutated melanoma cells, it increased the effectiveness of the vemurafinib treatment.

“Our finding that loss of the tumor suppressors STAG2 or STAG3 is a novel genetic mechanism of BRAF inhibitor resistance also revealed an unexpected link between those proteins and the MAPK cell-growth pathway, activation of which drives these tumors,” said corresponding study author Bin Zheng, PhD. “Understanding and overcoming resistance to BRAF inhibition remains a major challenge facing the melanoma field. Identifying biomarkers capable of predicting response to BRAF inhibitor drugs — such as vemurafenib and dabrafenib – will facilitate early identification of patients likely to benefit from treatment and enable monitoring the development of resistance, which would allow consideration of other treatment options prior to relapse.

“The observations that mutations of STAG2 and STAG3 can lead to reactivation of the MAPK pathway was a novel and unexpected finding of our study. We are not working to identify vulnerabilities in STAG2/3 mutant melanomas and discover new approaches to targeting these tumors, which we hope will provide new insight into both preventing BRAF inhibitor resistance and treating tumors that have become resistant.”