All in the epigenetics

Team finds epigenetic reason for drug resistance in deadly melanoma and identifies potential ways to counteract it

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NEW YORK—In late August, Mount Sinai researchers discovered a previously unknown reason for drug resistance in a common subtype of melanoma, one of the deadliest forms of cancer. Even better, they have found a new therapy that could prevent or reverse drug resistance for melanoma patients with a particular gene mutation, according to a study published in Nature Communications.
The scientists identified a novel epigenetic mechanism that causes resistance to the standard treatment in melanoma patients with mutations in the BRAF genes, which are found in about half of all melanomas.
As lead researcher Dr. Emily Bernstein, associate professor in the Departments of Oncological Sciences & Dermatology, Icahn School of Medicine at Mount Sinai, tells DDNews, “BRAF mutant melanoma is sensitive to BRAF and MEK inhibitors, but the tumors return. This resistance can be driven by genetic alterations, but the epigenetic factors were unknown. Through an unbiased screen focused on epigenetic factors, we identified SIRTUIN6 as a key player. Importantly, we found that levels of SIRT6 have differential effects on drug resistance.”
Researchers also found a biomarker, or a biological signature that accompanies this drug resistance: a gene called IGFBP2, which is also associated with poor prognosis in melanoma patients.
“First, high IGFBP2 levels may indicate high likelihood for resistance in BRAF-mutant patients given BRAF + MEK inhibitors. Second, that BRAF inhibition plus IGF signaling inhibitors can inhibit tumor growth of resistant melanoma cells,” Bernstein notes.
Patients with high levels of IGFBP2 could benefit from combination therapies, which could be created in response to these findings, that inhibit BRAF mutations and IGFBP2-driven biological pathways as a multi-pronged approach to preventing drug resistance or reversing it once it has occurred, the study shows.
“Here you would block simultaneously the mutation effects and the pathways that could cause resistance,” Bernstein continues. “IGF1R/IR inhibitors could be very useful when used in combination with other therapies such as BRAF or MEK inhibitor to impede resistance.”
Other studies show the potential to find IGFBP2 via urine samples, so the implications for detection and later treatment are large. Bernstein says the next step for this line of research will be “understanding the role of additional epigenetic factors identified in the screen. Chromatin modifiers are key players in the drug resistance mechanisms of tumor cell behavior.”
According to the study, “Mechanisms of MAPKi resistance in BRAFV600-mutant melanoma have mainly focused on components of the ERK signalling pathway; however, little is known about the epigenetic regulators involved in this process. We hereby present a chromatin-focused CRISPR-Cas9 screen to identify factors that play a critical role in BRAFV600-mutant melanoma resistance to MAPKi, and identified enzymes that mediate histone acetylation. We found that SIRT6 haploinsufficiency in BRAFV600E melanoma cells decreases sensitivity to MAPKi, independent of the ERK signalling pathway. SIRT6 haploinsufficiency allows cells to survive via IGFBP2 expression, which in turn activates IGF-1R and downstream AKT signalling in the presence of MAPKi.”
“The link between SIRTUINs and IGF signalling has been reported in multiple systems,” the study continues. “For example, SIRT6 acts at the chromatin level to regulate the transcriptional status of insulin/IGF-AKT signalling-related genes to prevent cardiac hypertrophy and heart failure. Previous studies have also implicated increased activation of the AKT signalling pathway in promoting MAPKi resistance. Interestingly, Villanueva et al. reported IGF-1R/PI3K signalling to play a role in MAPKi resistant melanoma and hypothesized that additional factors (e.g. IGFBPs) were essential to engage this process. Here, through an unbiased screening approach, we identified SIRT6-mediated transcriptional regulation of IGFBP2, and consequent activation of IGF-1R/AKT, to play a role in melanoma MAPKi resistance. Therefore, we provide a deeper mechanistic understanding of the upstream activators of IGF1R/AKT signalling in this process.”
“The incidence of cutaneous malignant melanoma is rising, and its therapeutic management remains challenging,” says Bernstein. “In recent years, there has been extensive therapeutic development to inhibit key biological targets. Although a large proportion of patients with advanced metastatic melanoma harboring BRAF mutations respond to the standard therapy, known as MAPK inhibitors, subsequent resistance remains a major clinical challenge.”
“Finally, a recent study identified IGFBP2 as part of a gene signature in response to MAPKi in a population of cells referred to as drug-tolerant persisters. Importantly, the burden of acquired melanoma resistance emerges from such tumor subpopulations. Thus, early treatment to eradicate this population is key to delay or prevent drug resistance,” the study adds. “While IGFBP2 is overexpressed in various tumors, including melanoma, and is part of a gene signature of MAPKi drug tolerant persistors, there is little evidence for its use as a biomarker. We observed that IGFBP2 protein levels correlated with resistance to MAPKi in several BRAFV600-mutant melanoma cell lines, and is associated with poor prognosis in primary melanomas. Interestingly, IGFBP2 has been implicated as a candidate diagnostic for heart failure with a high sensitivity and specificity by urine proteomic analyses, clearly highlighting its use as a potential biomarker for melanoma MAPKi resistance. In sum, our data strongly suggest that co-targeting of MAPK and IGF-1R pathways can prevent/delay resistance to targeted MAPKi therapies, particularly for patients with high levels of IGFBP2.”

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