Search bioRxiv⌕ Search
Home/Archive/bioRxiv

bioRxiv · 10.64898/2026.07.17.738886

Cisplatin-Induced Plasticity Drives Cross-Resistance to CDK4/6 Inhibitors and Reveals Targetable Vulnerabilities Through HDAC Inhibition in Esophageal Squamous Cell Carcinoma.

Avalos-Moreno, M.·Vigato, A.·Moresi, F.·Japon-Ruiz, D.·Beck, B.·Bisteau, X.
View original source ↗Export metadata ↓

Abstract

Esophageal squamous cell carcinoma (ESCC) accounts for 90% of esophageal cancer cases worldwide and carries a poor prognosis, with overall survival below 20%. Chemotherapy remains the standard of care, yet acquired resistance is a critical barrier and the programs that establish and stabilize it are still poorly defined. Using an in vitro model of cisplatin resistance, we show that sustained platinum exposure does not drive a single, uniform resistant state but a continuum of adaptive transcriptional states. Most resistant clones presented a drug-tolerant persister (DTP)-like phenotype with stemness traits and slow-cycling behaviour. The DTP phenotype persisted after cisplatin withdrawal and was accompanied by markers of resistance, suggesting consolidation into a stable, acquired-resistance state. Unexpectedly, the effect of this reprogramming extended beyond cisplatin. Resistant clones displayed impaired cytostatic control and failed to suppress cell cycle programs upon CDK4/6 inhibition (CDK4/6i), revealing collateral cross-resistance. Multiomic profiling revealed an attenuation of the immune and inflammatory signaling expected from CDK4/6i, upregulation of immune-evasive markers and a dysregulated IFN pathway activation at baseline in cisplatin-resistant clones, reflecting an immune-evasive state consequent to cisplatin-induced reprogramming. A signature-based approach identified HDAC inhibitors as candidates for reversing resistance, and functional validation confirmed that HDACi combined with cisplatin fully restored parental-level sensitivity while also enhancing CDK4/6i efficacy, supporting epigenetic reprogramming as a strategy to counteract cross-resistance. Together, our findings define cisplatin resistance in ESCC as a reversible, epigenetically encoded and immune-evasive state, and provide a mechanistic rationale for HDACi-based combinations to restore sensitivity to both cisplatin and CDK4/6 inhibitors. Statement of SignificanceSustained cisplatin exposure drives esophageal squamous cell carcinoma toward a drug-tolerant persister-like, immune-evasive state that survives drug withdrawal and confers cross-resistance to CDK4/6 inhibition. HDAC inhibition reverses this state, restoring sensitivity to both agents and synergizing in chemotherapy-naive cells, supporting epigenetic intervention early in treatment.

Explore related subjects

cancer biologyPreprint

Keep this discovery

Explore connections, maps & timelines

BibTeXRIS

Avalos-Moreno, M., Vigato, A., Moresi, F., Japon-Ruiz, D., Beck, B., Bisteau, X.. 2026-07-17. Cisplatin-Induced Plasticity Drives Cross-Resistance to CDK4/6 Inhibitors and Reveals Targetable Vulnerabilities Through HDAC Inhibition in Esophageal Squamous Cell Carcinoma.. https://doi.org/10.64898/2026.07.17.738886

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related preprints

bioRxiv2026

Tet2-Clonal Hematopoiesis Promotes Whereas Dnmt3a-CH Inhibits Breast Cancer Progression During Aging

Clonal hematopoiesis of indeterminate potential (CHIP) driven by somatic mutations in blood cells increases with age and is associated with adverse outcomes in cancer patients. How CHIP mutations influence solid tumor progression remains unclear. Using inducible murine models of Dnmt3a- or Tet2-mutant CHIP combined with orthotopic syngeneic breast cancer models, we demonstrate that upon aging Dnmt3a-mutant CHIP prevents whereas Tet2-mutant CHIP drives breast cancer progression. Dnmt3a-mutant immune infiltrates established interferon-mediated MHCIIhigh tumor-associated macrophages (TAMs) that supported cytotoxic CD8+ T cell-mediated tumor rejection. In contrast, Tet2-mutant TAMs exhibited an inflammatory, immunosuppressive phenotype characterized by increased IL-1 and CXCL2 production, reduced MHCII expression, and impaired T cell recruitment and activation. Therapeutic blockade of IL-1R1 or CXCR2 reduced tumor progression in aged Tet2-mutant CHIP mice and partially restored anti-tumor immunity. These findings establish that the effects of CHIP on cancer are mutation- and age-dependent and identify IL-1/CXCL2-driven inflammation as a therapeutic vulnerability of tumor-promoting Tet2-mutant CHIP.

cancer biology↗
bioRxiv2026

Single Nucleus Profiling Reveals Rewired Tumor-Immune-Stromal Cell Communication in Plasmacytoid Urothelial Carcinoma

Plasmacytoid urothelial carcinoma (PUC) is an aggressive histologic subtype of bladder cancer associated with worse patient outcomes and therapeutic response compared to conventional urothelial carcinoma (CUC). While recent work has demonstrated metastatic lymph nodes from PUC tumors have an inflamed phenotype, how the tumor microenvironment (TME) and crosstalk between tumor, stromal, and immune cells in primary PUC bladder tumors differs from those in CUC remains poorly understood. The impact of these differences on response to immunotherapy is also unknown. To understand TME differences between CUC and PUC and their impact on cell signaling, we performed single nucleus RNA sequencing on PUC and CUC tumors, as well as Xenium spatial transcriptomics on a mixed CUC / PUC tumor. We identified increased signaling between PUC-enriched, CDH1-low urothelial cells, immunosuppressive lipid-associated macrophages, and SFRP2+/CTHRC1+ fibroblasts in PUC tumors compared to CUC. Spatial transcriptomics identified increased macrophage infiltration in PUC histology and colocalization of PUC tumor cells, immunosuppressive macrophages, and SFRP2+ fibroblasts. Taken together, this study delineates PUC architecture and demonstrates interplay CDH1-low tumor cells, EMT, and immunosuppressive macrophages, identifying possible therapeutic vulnerabilities in PUC.

cancer biology↗
bioRxiv2026

The Phospholipase A2 Activity of Peroxiredoxin 6 Protects Hepatocarcinoma Cells Against Ferroptosis and Mitophagy Impairment

Peroxiredoxin 6 (PRDX6) is a moonlighting protein that plays a key role in regulating redox homeostasis and lipid metabolism through its unique dual peroxidase and calcium-independent phospholipase A2 (iPLA2) activities. Here, we generated a stable HepG2 cell line harboring a D140A mutation to selectively ablate iPLA2 activity, and we compared its phenotype with that of wild-type (WT) and PRDX6-knockout (KO) cells. D140A exhibited low ROS leves, similar to WT cells, confirming that oxidative stress is due to peroxidase deficiency. In contrast, D140A cells displayed higher lipid peroxidation than WT cells, though significantly lower than that of KO cells. Furthermore, the D140A mutant mirrored the KO phenotype regarding intracellular ferrous iron accumulation, impaired lipid droplet biogenesis, and the downregulation of the key ferroptosis regulator GPX4. Mechanistically, integrated proteomic, lipidomic, and enzymatic analyses revealed that a deficiency in iPLA2 activity of PRDX6 disrupted the release of key lipid species necessary for cell structure and signaling. Consequently, organelles involved in lipid synthesis and trafficking, such as peroxisomes, endoplasmic reticulum, mitochondria and lipid droplet, were affected. Specifically, we found that mitochondria exhibited a reduction in cristae and a diminished capacity for mitophagy and autophagy, which ultimately makes cells much more susceptible to erastin-induced ferroptotic cell death. Taken together, our findings demonstrate that PRDX6 iPLA2 activity uniquely coordinates organelle lipid homeostasis and mitophagy to protect cancer cells from ferroptotic cell death. Consequently, the use of iPLA2 inhibitors such as MJ33, which decreased PRDX6 iPLA2 activity to a level comparable to the mutant D140A, could represent a promising therapeutic strategy for inducing ferroptotic cell death in hepatocellular carcinoma.

cancer biology↗