Study Identifies Novel Treatment Resistance Mechanism in BRAF-Mutant Melanoma
A Massachusetts General Hospital (MGH) research team has identified an additional mechanism for resistance to targeted treatment for BRAF-mutant melanoma. Their findings, published by Shen et al in Nature Medicine, report that inactivating mutations in two genes responsible for regulating key aspects of cell division can reactivate the signaling pathway driving tumor growth that had been blocked by BRAF inhibitor drugs.
“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 Bin Zheng, PhD, of the Cutaneous Biology Research Center at MGH, Assistant Professor of Dermatology at Harvard Medical School, and corresponding author of the paper. “Understanding and overcoming resistance to BRAF inhibition remains a major challenge facing the melanoma field, and identifying intermediate biomarkers capable of predicting response to BRAF inhibition will facilitate early identification of patients likely to benefit from treatment and monitoring the development of resistance to allow consideration of other treatment options prior to relapse,” said Dr. Zheng.
In about half the cases of malignant melanoma, tumor growth is driven by mutations in the BRAF gene, and treatment of those tumors with drugs that inhibit BRAF activity can halt and sometimes reverse tumor growth. But treatment resistance almost invariably develops, leading to a resumption of tumor growth. Several mechanisms behind this resistance have been identified, including mutations in other genes in the MAPK pathway, of which BRAF is a component, that essentially circumvent the suppression of BRAF activity. But as many as 25% of cases of resistance to BRAF inhibitors do not involve identified mechanisms.
Study Findings
In their search for additional resistance mechanisms, the investigators first performed whole-exome sequencing of tumor samples from a patient taken before treatment and after the development of resistance to the BRAF inhibitor vemurafinib. A comparison of novel mutations in the post-resistance sample with a list of known cancer-associated mutations identified a single significant mutation in the tumor suppressor STAG2. That gene and related genes called STAG1 and STAG3 code for subunits of the cohesin complex, an assembly of proteins that regulates a key stage in cellular division and also may play a role in the regulation of gene expression. Several cohesin complex genes, including STAG3, are known to be mutated in other forms of cancer.
Examination of the levels of all three STAG proteins in a panel of treatment-resistant melanoma cell lines identified reduced expression of STAG2 and STAG3 in several cell lines, including lines resistant to inhibition of both BRAF and of MEK, another protein in the MAPK pathway. They identified what may be the responsible STAG2 mutation, and while they could not find any STAG3 mutation in their panel, examination of data from a published study of BRAF inhibitor treatment identified STAG3 mutations in pretreatment samples of tumors that developed early resistance to treatment.
Experiments in cultured melanoma cell lines and in tumors implanted into mice revealed that knockdown of the expression of either protein reduced sensitivity to BRAF inhibition by reactivating a later stage of the MAPK pathway. In contrast, increasing the expression of either STAG2 or STAG3 in BRAF-mutated melanoma cells increased the effectiveness of vemurafinib treatment. Dr. Zheng notes that exactly how the proteins exert their tumor suppressor functions in any type of cancer has yet to be determined.
“The observation that mutations of STAG2 or STAG3 can lead to reactivation of the MAPK pathway was a novel and unexpected finding of our study,” he said. “We are now 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.”
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