Cancer Cells Defy Quiescence Doctrine as MYC Drives a Proliferative Chemoresistance Program

Chemotherapy resistance remains one of the most stubborn obstacles in modern oncology, responsible in large part for the high mortality that continues to accompany many epithelial malignancies despite decades of drug development. For years, the dominant scientific narrative has held that tumor cells survive cytotoxic treatment by retreating into a quiescent, slow-cycling state or by adopting an epithelial-to-mesenchymal transition phenotype that renders them less vulnerable to drugs targeting proliferating cells. A new study published in Genome Medicine turns that narrative on its head. An international team led by Vijay K. Tiwari of the University of Southern Denmark, working with collaborators at the University of Maryland School of Medicine and Queen’s University Belfast, has uncovered a conserved molecular program of chemoresistance that operates across multiple cancer types—and it is fundamentally a program of hyperproliferation, not rest.

The research, whose first authors include Mohammed Inayatullah and Engin Demirdizen, integrated an unusually broad array of data modalities to address a question that has lingered in the field: whether conserved molecular programs underpin therapy resistance regardless of cancer type. The team combined single-cell RNA sequencing, spatial transcriptomics, regulatory network modeling, transcription factor binding data, and pharmacologic perturbation experiments. By layering these approaches across several cancer types, they were able to define what they describe as a pan-cancer, proliferative chemoresistant tumor state—a shared cellular identity that resistant cells from different organs appear to converge upon under the selective pressure of chemotherapy.

The technical findings are striking in their departure from expectation. Rather than exhibiting the low proliferative activity associated with quiescence, resistant tumor cells in the study displayed elevated G2/M and S-phase cell cycle signatures, indicating that they were actively progressing through DNA replication and mitosis at the time of or following treatment. Gene set analyses revealed enriched expression of E2F and MYC target genes, two transcriptional programs classically associated with driving cell cycle entry and growth. Alongside these, the resistant cells showed activation of DNA repair pathways, consistent with an enhanced capacity to mend the damage inflicted by genotoxic chemotherapy, and of PI3K/AKT signaling, a pro-survival axis that supports metabolism and continued proliferation even under stress.

Central to this resistant state, the researchers identified the transcription factor MYC as its master regulator. MYC, one of the most frequently dysregulated oncogenes in human cancer, showed progressive activation along the resistance trajectory—in other words, as cells moved toward a chemoresistant phenotype, MYC activity climbed steadily. Spatial transcriptomics added a clinically meaningful dimension: MYC expression was concentrated in focal pockets within resistant epithelial niches, suggesting that resistant cells do not emerge randomly throughout a tumor but cluster in specific microenvironments where the MYC-driven program is sustained. This spatial organization may explain why resistant clones can dominate recurrences so rapidly once first-line therapy fails.

Perhaps the most consequential discovery from the study concerns a previously underappreciated MYC target gene: SRM, which encodes spermidine synthase, an enzyme central to the biosynthesis of polyamines. The team found that SRM acts as a conserved effector of chemoresistance, promoting polyamine production that the resistant cells require for chromatin stability and metabolic resilience. Polyamines—putrescine, spermidine, and spermine—are small, positively charged molecules that bind nucleic acids and support numerous aspects of cell growth, but their specific role in maintaining the chromatin architecture of drug-resistant cells had not been defined in this context. The new data position SRM not merely as a downstream passenger but as a functional pillar of the resistant phenotype.

The clinical implications of the MYC–SRM axis were reinforced by survival analyses. SRM expression in patient tumors correlated with MYC binding at its regulatory regions and predicted poor patient survival, marking the enzyme as a potential biomarker of therapeutic failure as well as a target in its own right. When the authors examined whether this axis was merely correlative, the answer was emphatically no. Functional validation experiments spanning cancer cell lines, patient-derived organoids, and mouse models demonstrated that pharmacologic inhibition of MYC, of SRM, or of WNT signaling restored chemotherapy sensitivity, suppressed resistance-associated pathways, and reactivated apoptosis—the programmed cell death that chemotherapy is designed to trigger but that resistant cells evade.

What makes this work particularly compelling is the convergence of validation across model systems. Cell lines allow precise mechanistic dissection, but they can diverge from human disease. Patient-derived organoids, which retain much of the cellular heterogeneity and drug response of the original tumors, and in vivo mouse models provide stronger translational evidence. Demonstrating that disrupting the MYC–SRM module resensitizes tumors across all three platforms, and that spatial and survival analyses in human tissues confirm the axis’s clinical relevance, argues that this is a druggable vulnerability rather than a laboratory artifact. The authors go so far as to establish the MYC–SRM axis as a tractable module in treatment-refractory cancers, a claim supported by the pharmacologic tools already available against components of the polyamine biosynthesis pathway.

The conceptual reframing is equally significant. If chemoresistance is not principally a matter of cells going dormant but of cells rewiring themselves into an aggressive, MYC-driven proliferative and repair-competent state, then therapeutic strategies must be recalibrated. Approaches that simply target quiescent or mesenchymal phenotypes may miss the dominant biology of resistance. Conversely, combination regimens pairing conventional chemotherapy with inhibitors of MYC activity, spermidine synthase, or WNT signaling could in principle prevent the emergence or persistence of resistant clones by striking at the very engine of their survival. The finding that PI3K/AKT signaling and DNA repair programs are co-activated in the resistant state further suggests additional combination nodes for drug development.

There are, of course, well-known challenges ahead. MYC has long been considered notoriously difficult to drug directly, though indirect strategies—such as targeting MYC-dependent metabolic enzymes like SRM, or exploiting synthetic lethal interactions—have gained traction in recent years. The identification of SRM as a conserved, druggable effector downstream of MYC offers exactly the kind of actionable node that the field has sought: inhibiting a metabolic enzyme is far more tractable pharmacologically than inhibiting a transcription factor. Whether SRM inhibitors can be advanced safely into clinical combination trials, and whether the pan-cancer signature holds uniformly across all epithelial malignancies, will require prospective clinical validation. Nonetheless, the breadth of evidence assembled in this study—from single-cell and spatial genomics to organoids and animal models—makes a strong case that the MYC–SRM axis represents a genuine Achilles’ heel of chemotherapy-resistant tumors.

The study, funded by the Neye Foundation, the Novo Nordisk Foundation, the Danish National Research Foundation, the Danish Cancer Society, and ICURe grants, is among the first comprehensive efforts to redefine chemoresistance at a pan-cancer level using integrated single-cell and spatial technologies. By demonstrating that a single, conserved, MYC-orchestrated proliferative program underlies treatment failure across diverse cancer types, and by pinpointing spermidine synthase as a druggable linchpin of that program, the work offers oncologists a new conceptual map of resistance and a concrete therapeutic entry point. For patients whose tumors have exhausted standard options, the prospect of restoring chemotherapy sensitivity by dismantling this shared molecular machinery is a development worth watching closely in the years ahead.

Subject of Research: Pan-cancer molecular signatures of chemotherapy resistance and the MYC–SRM axis

Article Title: Uncovering pan-cancer signatures of chemoresistance

Article References: Inayatullah, M., Demirdizen, E., Keepers, Z., Correia, C. M., Hashemi, S. M., Tripathi, K., Sadhukhan, S., Bardhan, I., Mariappan, A., Rassool, F. V., Terp, M. G., Shukla, H. D., & Tiwari, V. K. (2026). Uncovering pan-cancer signatures of chemoresistance. Genome Medicine. https://doi.org/10.1186/s13073-026-01763-2

Image Credits: AI Generated

DOI: 10.1186/s13073-026-01763-2

Keywords: chemoresistance, MYC, SRM, spermidine synthase, single-cell RNA sequencing, spatial transcriptomics, pan-cancer, drug resistance, polyamine biosynthesis, E2F, PI3K/AKT signaling, Genome Medicine