Myelodysplastic syndromes (MDS) consist of a heterogeneous group of under-diagnosed rare group of bone marrow failure disorders. The annual age-adjusted incidence in the United States is approximately 4.5/100,000 persons, and the incidence substantially rises with age (Leukemia 2021; https://doi.org/10.1038/s41375-021-01265-7). With few therapeutic options, the overall 5-year survival probability remains dismal at approximately 38 percent, according to the Leukemia & Lymphoma Society. Thus, there remains an unmet clinical need for novel therapeutic strategies.
In a recent study published in Cancer Discovery, scientists at the Icahn School of Medicine at Mount Sinai and University California San Diego aimed to identify high-confidence targets and the driver of MDS (2021; doi: 10.1158/2159-8290.CD-21-0508). Mutations in splicing factors (SFs) are the predominant class of mutations in MDS, but their critical effectors remain unknown.
In the study, the team generated an isogenic induced pluripotent stem cell (iPSC)-derived model of SF-mutant MDS. Using this model, they utilized RNA-Seq and eCLIP to quantify alternative splicing and in vivo mRNA binding analysis to converge onto a new target for MDS.
The team identified the first direct target of convergent mis-splicing by mutant U2AF1 and SRSF2, a long GNAS isoform. The GNAS isoform encodes a hyperactive long form of the stimulatory G protein alpha subunit, Gas-L, that mediates ERK/MAPK pathway activation, thereby driving MDS and making mutant cells sensitive to MEK inhibitors. The findings suggest MEK inhibitors may be a viable therapeutic option for MDS patients with SRSF2 and U2AF1 mutations and can be targeted by drugs already approved by the FDA for treating other cancers.
Oncology Times connected with co-senior author Eirini Papapetrou, MD, PhD, Associate Professor of Oncological Sciences at the Icahn School of Medicine at Mount Sinai, for further insights into their study.
Oncology Times: What has been some of the challenges for effective treatments of MDS?
Papapetrou: "Current treatments for MDS are very suboptimal. The only curative treatment is allogeneic hematopoietic stem cell transplantation, but this option is available only to a very small fraction of patients, as the majority of MDS patients are not eligible due to advanced age and/or comorbidities.
"In MDS, patients with lower-risk disease treatments are aimed at relief of symptoms and reduction or elimination of red blood cell transfusions. These treatments include erythropoiesis-stimulating agents, lenalidomide for patients with del(5q) MDS, or luspatercept for patients with MDS with ring sideroblasts (MDS-RS). Azacitidine, a hypomethylating agent, is the standard of care for treatment of MDS patients with higher-risk MDS. Although responses occur, these are mainly transient, and the overwhelming majority of patients progress on any of these treatments. Crucially, drug development in the area of MDS is very limited currently with very few candidates in the pipeline progressing to clinical testing, compared to other cancers or hematologic malignancies."
Oncology Times: What were some critical features of this study that allowed you to identify GNAS as a high-priority direct target common to both mutant factors (MDS patients with SRSF2 and U2AF1 mutations)?
Papapetrou: "Two critical features of our study empowered our analytical approach and allowed us to zoom in on GNAS. First, the novel iPSC models of the mutations, that we created in our lab, provided human models with a genetically faithful context of the SRSF2 and U2AF1 mutations (i.e., without overexpression, but rather as heterozygous mutations in a diploid human genome), and the ability to derive relatively homogeneous populations of hematopoietic progenitor cells through directed in vitro differentiation for genomic analyses. They also provided isogenic conditions (e.g., availability of matched normal, WT, controls, and having both mutations in the same genetic background) that empowered the search for common mis-spliced gene target.
"The second critical feature was an improved method to map RNA-protein interactions, called enhanced CLIP or eCLIP, that the partner laboratory of Gene Yeo, PhD, in UCSD, developed and applied to this study. This method gave us an additional layer of information that was missing from previous studies, namely the exact regions of specific genes on which the mutant splicing factors (U2AF1 and SRSF2) bind less or more, compared to the normal unmutated factors. This allowed us to narrow down the candidate genes that are directly mis-spliced by the mutant factors and identify GNAS as an important target."
Oncology Times: How significant is the ability to repurpose current FDA-approved MEK inhibitors for targeting GNAS in this cancer?
Papapetrou: "Our study suggests that mis-splicing of GNAS activates signaling and renders mutant cells sensitive to MEK inhibitors (MEKi). Given the scarcity of therapeutic options for MDS patients, discussed above, and the strong impetus that comes with testing a drug that is already FDA-approved for different indications, the prospect of testing MEKi in MDS patients with splicing mutations is tempting."
Oncology Times: What are the current limitations of this study and what are the next steps?
Papapetrou: "Out study was based on iPSC models and our findings were confirmed in primary cells from MDS patients. Still, we need to dissect the signaling consequences of GNAS mis-splicing in more detail, which could provide additional therapeutic opportunities. We also need to confirm our findings in a larger study of primary MDS cells and, ultimately, the importance of the findings would need to hold in clinical testing. GNAS itself could be another attractive target for new therapeutics, which could be developed on the future."
Dibash Kumar Das is a contributing writer.