A hidden vulnerability in pancreatic cancer opens the door to targeting an “undruggable” oncogene

Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers, partly because the oncogenes driving tumor growth have been historically difficult to target. Many PDAC tumors are driven by amplified copies of the MYC oncogene, a transcription factor that boosts cell proliferation but has long been considered an undruggable transcription factor due to lack of an obvious small-molecule binding site. A new study led by Erin Ramsey and senior scientist Dr. Patick Carroll in the Eisenman lab at Fred Hutch reveals an unexpected vulnerability in these MYC-addicted tumors and tests a small-molecule drug to exploit it. Their findings were recently published in PNAS.

The MYC protein doesn't work alone. It operates within a larger transcription factor network that includes mitogenic regulators (MAX) and nutrient-sensing regulators (MondoA-MLX and ChREBP-MLX). The researchers focused on MondoA, a glucose-sensing transcription factor that forms a heterodimer with the transcription factor MLX. They asked whether MYC-amplified PDAC cells depend on MondoA for survival.

“Our lab had earlier reported a synthetic lethal dependency of deregulated MYC on MondoA in neuroblastoma. In collaborative studies with the Kugel lab in Human Biology we have now extended this observation to PDAC, a malignancy where MYC alterations lead to poor outcome and decreased survival,” Dr. Carroll shares. They found that knocking down MondoA with siRNA selectively killed MYC-amplified PDAC cell lines while leaving low-MYC-expressing lines largely unaffected. Overexpressing MYC in a non-MYC-amplified line was sufficient to confer sensitivity to MondoA knockout, confirming that the dependency is MYC-driven rather than cell-line-specific.

To understand why MondoA loss is lethal in this context, the team performed RNA-seq and CUT&RUN genomic occupancy profiling after MondoA silencing. They found increased expression of inflammatory pathways, including TNFα signaling and the unfolded protein response (UPR) and decreased expression of the DNA damage response and interferon signaling. Their studies revealed that MondoA directly binds roughly one thousand gene promoters, but its loss disrupted expression of far more genes, including thousands of MYC-bound genes. Profiling occupancy of MYC and MYC-network transcription factors MNT and ChREBP revealed the vast consequences of MondoA loss—reorganization of the entire network. Specifically, MYC and MNT binding at stress-response gene promoters dropped by roughly 20–25%, and MondoA's paralog ChREBP swooped in to fill some of those vacated sites, creating widespread transcriptional dysregulation across metabolic and stress pathways.

How exactly do these changes lead to PDAC lethality? It boils down to MondoA keeping MYC-induced cellular stress under control. The authors looked further into their finding that silencing MondoA leads to increased expression of genes in the UPR pathway. The UPR is one branch that feeds more generally into the cell’s integrated stress response (ISR), which converges on a key regulatory event: phosphorylation of the translation initiation factor eIF2α. This phosphorylation globally suppresses protein synthesis while simultaneously allowing selective translation of specific mRNAs such as ATF4, the master transcription factor the cell needs to decide whether to adapt to stress or undergo apoptosis. In MYC-amplified cells, the high biosynthetic demand created by MYC chronically stresses the cell, making a functional ISR essential for survival; essentially, MYC creates proteostatic chaos and forces the cell to rely on ATF4 to manage the cleanup.

Using a drug that induces the UPR, the authors discovered that MondoA is required for the drug to induce expression of the ATF4. When MondoA is lost, the cell is unable to mount a stress response because MondoA is required for proper ATF4 protein translation. The researchers traced this to disruption of the m6A RNA methylation pathway, specifically, downregulation of FTO, an RNA demethylase that normally facilitates ATF4 translation. Critically, restoring ATF4 protein expression was sufficient to rescue cell viability after MondoA knockdown, providing direct causal evidence for the mechanism.

Lead author Erin Ramsey expands upon these results: “We went into these experiments expecting MYC-amplified PDAC cells to rely on MondoA because of the latter’s role as a transcription factor (TF) directly binding and regulating expression of critical target genes in collaboration with MYC. What we found, however, was that MondoA promoter binding accounted for very little of its role in these cells. This forced us to widen our understanding of what MondoA can do and uncovered its role in regulating the binding of other TFs, activating the Integrated Stress Response, and balancing mRNA methylation and processing. It serves as a good reminder that proteins rarely have just one function, and that to truly understand what they are doing in a cell we have to look beyond their previously characterized roles.”

Because MondoA-MLX nuclear translocation can be blocked by small molecules, the team tested two of these, SBI-477 and its more bioactive derivative SBI-993, in both cell lines and patient-derived organoids (PDOs). Six of seven PDAC PDOs responded to SBI-993 treatment, with faster-growing organoids showing the greatest sensitivity. Finally, the authors looked at clinical data from PDAC patients. They created gene expression signatures from MondoA-inhibited cells and found that patients with high expression of these signatures had improved overall survival.

Together, these results imply that MondoA represents an indirect but actionable route to targeting MYC, one that unravels the very stress addiction loop that MYC amplification creates. “This work defines a druggable route to targeting unbridled MYC activity in PDAC lines and organoids via chemical inhibition of MondoA transcriptional activity, thus opening a novel therapeutic window with what we believe to be widespread potential to target other MYC-driven malignancies,” Dr. Carroll concludes.

Fred Hutch/University of Washington/Seattle Children’s Cancer Consortium Members Drs. Sita Kugel and Robert Eisenman contributed to this research.

The spotlighted research was funded by a Stuart and Molly Sloan Precision Oncology Institute Ignition Award, the National Institutes of Health, an American Cancer Society Postdoctoral fellowship, a Walter Benjamin Fellowship from the German Research Foundation, the Fred Hutch/University of Washington/Seattle Children’s Cancer Consortium and the Office of Research Infrastructure Programs.

Ramsey EL, Dobersch S, Freie B, Hong NH, Wu X, Kugel S, Eisenman RN, Carroll PA. 2026. MondoA mediates transcriptional coordination between the MYC network and the integrated stress response in pancreatic cancer. Proc Natl Acad Sci. doi: 10.1073/pnas.2524659123.