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bioRxiv2026

Neuroepithelial reprogramming and ERBB vulnerability in canine acanthomatous ameloblastoma

Canine acanthomatous ameloblastoma (CAA) is a locally invasive benign oral neoplasm that is difficult to distinguish from canine oral squamous cell carcinoma (COSCC) due to overlapping clinical, radiologic, and histologic features. Although both tumors exhibit MAPK pathway activation, their mutational landscapes are distinct. Furthermore, previous studies using bulk RNA sequencing (RNA-seq) have demonstrated pronounced differences in programs related to, among others, hypoxia, PI3K-AKT signaling, and cell proliferation. However, these bulk studies lacked the resolution to elucidate the cellular heterogeneity of CAA relative to COSCC. We therefore performed single-nucleus RNA-seq to define the cellular gene expression landscape of CAA, COSCC, and healthy gingiva. Across [~]205,000 nuclei, we identified major epithelial, immune, endothelial, and mesenchymal populations, as well as two epithelial subtypes uniquely enriched in CAA. The CAA-specific keratinocytes exhibited a neuronal-like expression program defined by synaptic regulators, KRAS-associated signaling pathways, and markedly elevated expression of PEG3, ERBB4, GABRB1, MAGI2, and CASK. These findings were validated by bulk RNA-seq, qPCR, and immunohistochemistry, which demonstrated strong nuclear localization of PEG3 exclusively in CAA epithelium. A kinase inhibitor screen independently identified ERBB4 as a candidate therapeutic vulnerability, and pharmacologic inhibition with neratinib was effective. Together, these findings reveal a previously unrecognized neuroepithelial cell state that defines CAA, distinguishes it from COSCC, and reveals unique diagnostic and therapeutic signaling dependencies. Given the molecular and histopathologic parallels between CAA and human ameloblastoma, these data further position CAA as a naturally occurring comparative model for studying ameloblastoma biology and therapeutic vulnerabilities. Significance StatementCanine acanthomatous ameloblastoma (CAA) is a common locally aggressive oral neoplasm often misdiagnosed as canine oral squamous cell carcinoma (COSCC) due to overlapping clinical, radiologic, and histologic features. Using single-nucleus RNA sequencing of CAA, COSCC, and healthy gingiva, we resolve the microenvironment of these tumors and detect two epithelial subpopulations unique to CAA. These CAA-specific keratinocytes exhibit a neuroepithelial-like signature characterized by synaptic regulators, KRAS-associated signaling, and elevated PEG3 and ERBB4 expression. Functional kinase inhibitor screening of patient derived microtumor slices independently converged on ERBB4 as an effective therapeutic target. Together, our study provides a molecular framework for distinguishing CAA from COSCC and establishes a comparative oncology model with translational relevance to human ameloblastoma and other ERBB-driven epithelial neoplasms.

cancer biology↗

bioRxiv2026

Coupled Modeling of Tumor Volume and ctDNA Dynamics in HPV-Associated Anal Squamous Cell Carcinoma

Response to anti-PD-1 immunotherapy in advanced HPV-associated anal squamous cell carcinoma (ASCC) varies and is assessed by infrequent imaging that lags behind tumor biology. Circulating tumor DNA (ctDNA) can be sampled frequently and reflects near-real-time tumor activity yet is rarely built into mechanistic models of treatment response. Using longitudinal tumor volume and HPV ctDNA from 26 patients treated with pembrolizumab, we found that baseline ctDNA scores tracked tumor burden but did not distinguish responders from non-responders, whereas ctDNA after one treatment cycle had a higher relative decrease in responders, six weeks before the next scan. We developed an ordinary differential equation model linking tumor volume to the ctDNA released by tumor cells. Sensitivity, identifiability, and model-selection analyses reduced it to two patient-specific parameters, proliferation and shedding rates, which reproduced individual volume and ctDNA trajectories, including a transient ctDNA spike at treatment onset. Proliferation was faster in non-responders. This framework supports model-based, ctDNA-guided monitoring of immunotherapy response.

cancer biology↗

bioRxiv2020

Run for your life: an integrated virtual tissue platform for incorporating exercise oncology into immunotherapy

The purpose of this paper is to introduce a novel in silico platform for simulating early stage solid tumor growth and anti-tumor immune response. We present the model, test the sensitivity and robustness of its parameters, and calibrate it with clinical data from exercise oncology experiments which offer a natural biological backdrop for modulation of anti-tumor immune response. We then perform two virtual experiments with the model that demonstrate its usefulness in guiding pre-clinical and clinical studies of immunotherapy. The first virtual experiment describes the intricate dynamics in the tumor microenvironment between the tumor and the infiltrating immune cells. Such dynamics is difficult to probe during a pre-clinical study as it requires significant redundancy in lab animals and is prohibitively time-consuming and labor-intensive. The result is a series of spatiotemporal snapshots of the tumor and its microenvironment that can serve as a platform to test mechanistic hypotheses on the role and dynamics of different immune cells in anti-tumor immune response. The second virtual experiment shows how dosage and/or frequency of immunotherapy drugs can be optimized based on the aerobic fitness of the patient, so that possible adverse side effects of the treatment can be minimized.

cancer biology↗

bioRxiv2014

Perturbation biology models predict c-Myc as an effective co-target in RAF inhibitor resistant melanoma cells

Systematic prediction of cellular response to perturbations is a central challenge in biology, both for mechanistic explanations and for the design of effective therapeutic interventions. We addressed this challenge using a computational/experimental method, termed perturbation biology, which combines high-throughput (phospho)proteomic and phenotypic response profiles to targeted perturbations, prior information from signaling databases and network inference algorithms from statistical physics. The resulting network models are computationally executed to predict the effects of tens of thousands of untested perturbations. We report cell type-specific network models of signaling in RAF-inhibitor resistant melanoma cells based on data from 89 combinatorial perturbation conditions and 143 readouts per condition. Quantitative simulations predicted c-Myc as an effective co-target with BRAF or MEK. Experiments showed that co-targeting c-Myc, using the BET bromodomain inhibitor JQ1, and the RAF/MEK pathway, using kinase inhibitors is both effective and synergistic in this context. We propose these combinations as pre-clinical candidates to prevent or overcome RAF inhibitor resistance in melanoma.

Cancer Biology↗

bioRxiv2026

Clear cell renal cell carcinoma consensus transcriptomic programs reveal converging trajectories towards aggressive disease

Clear cell renal cell carcinoma (ccRCC) is characterized by a branching genomic trajectory in which early biallelic VHL inactivation splits into PBRM1- and BAP1-mutant lineages. However, driver mutations alone do not account for the molecular and phenotypic heterogeneity. To dissect this heterogeneity, we developed a non-negative matrix factorization (NMF)-based gene expression analytical framework for identifying recurrent transcriptional programs across factorization dimensionalities and across datasets. We applied it to three curated datasets (IMmotion151, n = 823; JAVELIN Renal 101, n = 726; TCGA, n = 614) to define 17 consensus transcriptomic programs (CTPs). Mapping CTPs onto single-cell RNAseq (scRNAseq) of human ccRCC tumors and patient-derived tumorgraft models linked these programs to their cellular sources, distinguishing RCC-intrinsic, tumor-cell-extrinsic, and mixed programs. RCC-intrinsic CTPs associated with canonical drivers, including VHL (R1), PBRM1 (R2), BAP1 (R4), PTEN/TSC1 (R3), TFE3/TFEB fusions (R5), NF2 (R6), and CDKN2A/TP53 (MP-Prolif). Additional CTPs captured tumor microenvironment (TME) composition (TME-Tcell, TME-Myelo, TME-Endo, TME-Stroma) and biological processes active across multiple cellular compartments, including proliferation, Y-chromosome-linked expression in male tumors, ciliary biology, and translation. Trajectory inference methods revealed PBRM1-like and BAP1-like branches that converged on a shared aggressive late transcriptomic stage (TS) associated with higher nuclear grade, additional driver alterations, myeloid/stromal infiltration, and poor clinical outcomes. Spatial transcriptomics (and multiregional sequencing) of paired conventional ccRCC and sarcomatoid regions linked TS advancement with morphological progression and clonal evolution. After adjusting for stage, grade, and BAP1/PBRM1 status, TS remained independently prognostic. Furthermore, our data suggest that immune checkpoint inhibitor combinations are particularly beneficial for MP-Prolif and not R1 utilizing specimens. In summary, we present an atlas of recurring transcriptomic programs in RCC and an ontological framework bridging genotype, tumor-cell-intrinsic gene expression, and microenvironment remodeling, with implications for risk stratification and treatment selection in ccRCC.

Cancer Biology↗

bioRxiv2021

The eukaryotic translation initiation factor eIF4E reprogrammes the splicing machinery anddrives alternative splicing

Aberrant RNA splicing contributes to the pathogenesis of many malignancies including Acute Myeloid Leukemia (AML). While mutation is the best described mechanism underpinning aberrant splicing, recent studies show that predictions based on mutations alone likely underestimate the extent of this dysregulation. Here, we show that elevation of the eukaryotic translation initiation factor eIF4E reprogrammes splicing of nearly a thousand RNAs in model cell lines. Further, in AML patient specimens which did not harbour known splice factor mutations, [~]4000 transcripts were differentially spliced based on eIF4E levels and this was associated with poor prognosis. Inhibition of eIF4E in cell lines reverted the eIF4E-dependent splice events examined. Splicing targets of eIF4E act in biological processes consistent with its role in malignancy. This altered splicing program likely arose from eIF4E-dependent increases in the production of spliceosome components including SF3B1 and U2AF1 which are frequently mutated in AML. Notably, eIF4E did not drive mutation of these factors, only their production. eIF4E also physically associated with many splice factors including SF3B1, U2AF1, and UsnRNAs. Interestingly, eIF4E interacted with both pre-mRNA splicing substrates as well as the resulting product RNAs suggesting that eIF4E could chaperone RNAs throughout splicing as well as other aspects of post-splicing transcript regulation. Importantly, many eIF4E-dependent splice events differed from those arising from splice factor mutation and were more extensive highlighting that these splicing profiles arise from distinct, but potentially overlapping, mechanisms. In all, our studies provide a paradigm for how dysregulation of a single factor, eIF4E, can reprogramme splicing.

cancer biology↗

bioRxiv2026

Cross-species Study of Canine and Human Peripheral Nerve Sheath Tumors: Clinical and Molecular Perspectives

Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive sarcomas. An obstacle to treating MPNSTs is a lack of effective systemic therapies. Although over 70% of human MPNSTs have lost or inactivated the epigenome regulator polycomb repressive complex 2 (PRC2), its activity and contribution to canine PNST progression remain unclear. This study compared canine peripheral nerve sheath tumors (PNSTs) and human MPNSTs across biological and clinical features, including PRC2 activity. Immunohistochemical analysis was performed for a human tissue microarray of 54 neurofibromas and 139 MPNSTs, and 63 canine PNSTs for H3K27me3, a repressive histone mark deposited by intact PRC2, and H3K27ac, which increases globally upon H3K27me3 loss. To understand the genomic alterations present in canine PNSTs, we analyzed tumor mutation burden, copy number alteration, and transcriptomes of eight canine PNST/normal pairs. The results suggested that H3K27me3 loss and associated gain of H3K27ac epigenetically drive human and canine tumors. These findings warrant further studies to evaluate whether these epigenetic deregulations alter similar gene signatures across species.

cancer biology↗

bioRxiv2025

Single-Cell Analysis of Meningiomas Reveals Mutation-Associated Tumor and Immune Cell Gene Expression Programs

Genomic and epigenetic profiling, particularly DNA methylation analysis, have refined the molecular classification of meningiomas and revealed marked intratumoral heterogeneity. To further characterize heterogeneity within and between patients, we analyzed meningiomas using single-cell RNA sequencing (n=11), whole-exome sequencing (n=9), and spatial transcriptomics (n=3). Single-cell analysis revealed six transcriptionally distinct tumor cell states that corresponded to unique biological processes. Integration of the single-cell data with published exome and bulk RNA sequencing data from a large cohort revealed significant associations among somatic variants, tumor cell states, and immunological signatures. Notably, NF2-altered tumors were enriched for an epithelial-to-mesenchymal transition (EMT) cell state and immune cells, whereas NF2-intact tumors were enriched for a sterol metabolism cell state. Spatial transcriptomic analysis confirmed co-localization of immune cells and EMT tumor cells. Comparisons with immune cells from other brain tumors and peripheral tissues highlighted immunological cell states specific to meningioma. Collectively, these findings refine our genetic and molecular understanding of meningioma heterogeneity and underscore the link between genotype and molecular phenotype.

cancer biology↗

bioRxiv2024

Unveiling the Power of PROTAC Valency: Navigating Cell Type-Specific Hook Effects

Targeted protein degradation (TPD) using bivalent proteolysis-targeting chimeras (PROTAC) technology has shown potential in expanding the "druggable" proteome. In their publication in Nature Chemical Biology, Imaide et al.1 posited that augmenting PROTAC valency could potentially lead to the formation of long-lived ternary complexes between PROTAC, the protein of interest (POI), and E3 ligase, thereby constraining the formation of potent binary complexes, as evidenced by a pronounced hook effect. The authors introduced SIM1, a trivalent von Hippel-Lindau (VHL)-based PROTAC, which exhibited a superior degradation profile in comparison to its parent molecule MZ1, towards bromo and extra terminal (BET) proteins, with a predilection for BRD2. The authors attributed this heightened degradation capability of SIM1 over bivalent MZ1 as supportive evidence for their hypothesis. While we concur with the notion that increasing valency and avidity could enhance the efficacy of a PROTAC, the claim that trivalent PROTACs unequivocally eliminate the hook effect is not entirely accurate. We propose that the presence or absence of a hook effect is influenced by numerous factors beyond PROTAC valency.

cancer biology↗

bioRxiv2019

The diagnostic chronic lymphocytic leukaemia genome by nanopore sequencing

Chronic lymphocytic leukaemia (CLL) is characterised by considerable clinical and biological heterogeneity, with specific recurrent genomic alterations, including TP53 mutations, deletions of chromosome 17p, and IgHV mutational status, impacting on response to chemo-immunotherapy and targeted agents. Consequently, diagnostic screening for these predictive biomarkers is recommended in both national and international clinical guidelines. Current conventional methods, including fluorescent in-situ hybridisation and Sanger sequencing, exhibit shortcomings in terms of cost, speed and sensitivity, and even second-generation sequencing methods encounter technical limitations imposed by short-read lengths and bio-informatics analysis. The MinION platform from Oxford Nanopore Technologies generates exceptionally long (1-100kbp) read lengths in a short period of time and at low cost, making it a good candidate for diagnostic testing. In this paper, we present a nanopore-based CLL-specific screening assay, to simultaneously screen for both TP53 mutations and del17p13.1, as well as determining the IgHV mutation status for a single patient in one sequencing run. We sequenced 11 CLL patients and were able to generate a full diagnostic dataset for all. We identified somatic SNVs and indels in the coding region of TP53, and demonstrate that, following error correction of the data, we could accurately define the somatically hypermutated IgHV region in all patients. We also demonstrated the ability of the MinION platform to detect large-scale genomic deletions through low-coverage whole-genome sequencing. We conclude that nanopore sequencing has the potential to provide accurate, low-cost and rapid diagnostic information, which could be applied to other cancer types.

cancer biology↗

bioRxiv2021

Glioblastoma remodeling of neural circuits in the human brain decreases survival

Gliomas synaptically integrate into neural circuits. Prior work has demonstrated bidirectional interactions between neurons and glioma cells, with neuronal activity driving glioma growth and gliomas increasing neuronal excitability. In this study we wanted to know how glioma induced neuronal changes influence neural circuits underlying cognition and whether these interactions influence patient survival. We use intracranial brain recordings during lexical retrieval language tasks in awake humans in addition to site specific tumor tissue biopsies and cell biology experiments. We find that gliomas remodel functional neural circuitry such that task-relevant neural responses activate tumor-infiltrated cortex, beyond cortical excitation normally recruited in the healthy brain. Site-directed biopsies from functionally connected regions within the tumor are enriched for a glioblastoma subpopulation that exhibits a distinct synaptogenic and neuronotrophic phenotype. Tumor cells from functionally connected regions secrete the synaptogenic factor thrombospondin-1, which contributes to the differential neuron-glioma interactions observed in functionally connected tumor regions compared to tumor regions with less functional connectivity. The degree of functional connectivity between glioblastoma and the normal brain negatively impacts both patient survival and language task performance. These data demonstrate that high-grade gliomas functionally remodel neural circuits in the human brain, which both promotes tumor proliferation and impairs cognition.

cancer biology↗

bioRxiv2023

Ferredoxin 1 is essential for embryonic development and lipid homeostasis

Mammalian ferredoxin 1 and 2 (FDX1/2) belong to an evolutionary conserved family of iron-sulfur cluster containing proteins and act as electron shutters between ferredoxin reductase (FDXR) and numerous proteins involved in critical biological pathways. FDX1 is involved in biogenesis of steroids and bile acids, Vitamin A/D metabolism, and lipoylation of tricarboxylic acid (TCA) cycle enzymes. FDX1 has been extensively characterized biochemically but its role in physiology and lipid metabolism has not been explored. In this study, we generated Fdx1-deficient mice and showed that knockout of both alleles of the Fdx1 gene led to embryonic lethality. We also showed that like Fdxr+/- mice, Fdx1+/- mice had a shorter life span and were prone to steatohepatitis. However, unlike Fdxr+/- mice, Fdx1+/- mice were not prone to spontaneous tumors. Additionally, we showed that FDX1 deficiency led to lipid droplet accumulation possibly via the ABCA1-SREBP1/2 pathway. Specifically, untargeted lipidomic analysis showed that FDX1 deficiency led to alterations in several classes of lipids, including cholesterol, triacylglycerides, acylcarnitines, ceramides, phospholipids and lysophospholipids. Taken together, our data indicate that FDX1 is essential for mammalian embryonic development and lipid homeostasis at both cellular and organismal levels.

cancer biology↗

bioRxiv2026

Targeting proteasome composition reprograms tumor-intrinsic inflammation through selective degradation of STAT1

Proteasome regulatory particles determine cellular protein degradation capacities. Yet specific ubiquitin-independent degradation targets of individual proteasome regulatory particles, and physiological roles of such pathways, remain largely elusive. Here, through a chemical biology-driven approach, we identify a covalent small molecule that selectively targets a conformationally dynamic pocket in the non-catalytic proteasome regulator PSME4 and modulates tumor cell proteasome targets. Using this chemical probe together with orthogonal genetic perturbations, we show that blocking or reducing PSME4 stabilizes STAT1, restores interferon-associated transcription, enhances antigen presentation, and disrupts IL-6/STAT3 signaling, collectively reprogramming tumor inflammation and suppressing tumor growth in vivo. These findings define a PSME4-STAT1-STAT3 axis that couples proteasomal degradation to antigen presentation and cytokine signaling and provide a framework for pharmacologically targeting non-catalytic proteasome regulators to reprogram tumor immunity. More broadly, our findings reveal that proteasome composition can actively govern the balance between immunostimulatory and immunosuppressive signaling programs.

cancer biology↗

bioRxiv2021

Reciprocal impacts of telomerase activity and tumor cell differentiation in neuroblastoma tumor biology

Telomere maintenance and tumor cell differentiation have been separately implicated in neuroblastoma malignancy. Their mechanistic connection is unclear. We analyzed neuroblastoma cell lines and morphologic subclones representing the adrenergic (ADRN) and mesenchymal (MES) differentiation states and uncovered sharp differences in their telomere protein and telomerase activity levels. Pharmacologic conversion of ADRN into MES cells elicited consistent and robust changes in the expression of telomere-related proteins. Conversely, stringent down-regulation of telomerase activity triggers the differentiation of ADRN into MES cells, which was reversible upon telomerase upregulation. Interestingly, the MES differentiation state is associated with elevated levels of innate immunity factors, including key components of the DNA-sensing pathway. Accordingly, MES but not ADRN cells can mount a robust response to viral infections in vitro. A gene expression signature based on telomere and cell lineage-related factors can cluster neuroblastoma tumor samples into predominantly ADRN or MES-like groups, with distinct clinical outcomes. Our findings establish a novel mechanistic connection between telomere and differentiation and suggest that manipulating telomeres may suppress malignancy not only by limiting the tumor growth potential but also by inducing tumor cell differentiation and altering its immunogenicity.

cancer biology↗

bioRxiv2020

TET2 drives 5hmc marking of GATA6 and epigenetically defines pancreatic ductal adenocarcinoma transcriptional subtypes

Background and AimsPancreatic ductal adenocarcinoma (PDAC) is characterised by advanced disease stage at presentation, aggressive disease biology and resistance to therapy resulting in extremely poor five-year survival <10%. PDAC is classified into transcriptional subtypes with distinct survival characteristics, although how these arise is not known. Epigenetic deregulation, rather than genetics, has been proposed to underpin progression but exactly why is unclear and hindered by analysis of clinical samples. MethodsGenome-wide epigenetic mapping of DNA modifications 5-hydroxymethylcytosine (5mc) and 5-hydroxymethylcytosine (5hmc) using oxidative bisulphite sequencing (oxBS). Bioinformatics using iCluster and mutational profiling to identify overlap with transcriptional signatures in FFPE from resected patients and confirmation in vivo. ResultsWe find that more aggressive squamous-like PDAC subtypes result from epigenetic inactivation of loci including GATA6 that promote differentiated classical-pancreatic subtypes. We show that squamous-like PDAC transcriptional subtypes are associated with greater loss of 5hmc due to reduced expression of the 5mc-hydroxylase TET2. Furthermore, we find that SMAD4 directly supports TET2 levels in the pancreas and classical-pancreatic tumors and loss of SMAD4 expression is associated reduced 5hmc, GATA6 and squamous-like tumors. Importantly, enhancing TET2 stability using Metformin and VitaminC/ascorbic acid (AA) restores 5hmc and GATA6 levels, reverting squamous-like tumor phenotypes and WNT-dependence in vitro and in vivo. ConclusionsWe identify epigenetic deregulation of pancreatic differentiation as an underpinning event behind the emergence of transcriptomic subtypes in PDAC. Our data shows that restoring epigenetic control increases biomarkers of classical-pancreatic tumors and raises the possibility that combination of Vitamin C and Metformin may prolong survival in patients with squamous-like pancreatic cancer.

cancer biology↗

bioRxiv2021

Oncogenic RAS commandeers amino acid sensing machinery to aberrantly activate mTORC1 in multiple myeloma

Oncogenic mutations within the RAS pathway are common in multiple myeloma (MM), an incurable malignancy of plasma cells. However, the mechanisms of pathogenic RAS signaling in this disease remain enigmatic and difficult to inhibit therapeutically. We employed an unbiased proteogenomic approach to dissect RAS signaling in MM by combining genome-wide CRISPR-Cas9 screening with quantitative mass spectrometry focused on RAS biology. We discovered that mutant isoforms of RAS organized a signaling complex with the amino acid transporter, SLC3A2, and MTOR on endolysosomes, which directly activated mTORC1 by co-opting amino acid sensing pathways. MM tumors with high expression of mTORC1-dependent genes were more aggressive and enriched in RAS mutations, and we detected interactions between RAS and MTOR in MM patient tumors harboring mutant RAS isoforms. Inhibition of RAS-dependent mTORC1 activity synergized with MEK and ERK inhibitors to quench pathogenic RAS signaling in MM cells. This study redefines the RAS pathway in MM and provides a mechanistic and rational basis to target this novel mode of RAS signaling.

cancer biology↗

bioRxiv2024

Transcriptome-wide quantitative profiling of PUS7-dependent pseudouridylation by nanopore direct long read RNA sequencing

Understanding the interactions between different RNA modifications is essential for unraveling their biological functions. Here, we report NanoPsiPy, a computational pipeline that employs nanopore direct RNA sequencing to identify pseudouridine ({Psi}) sites and quantify their levels at single-nucleotide resolution. We validated NanoPsiPy by transcriptome-wide profiling of PUS7-dependent {Psi} sites in poly-A RNA and rRNA. NanoPsiPy leverages {Psi}-induced U-to-C basecalling errors in nanopore sequencing data, allowing detection of both low and high stoichiometric {Psi} sites. We identified 8,624 PUS7-dependent {Psi} sites in 1,246 mRNAs encoding proteins associated with ribosome biogenesis, translation, and energy metabolism. Importantly, integrative analysis revealed that PUS7 knockdown increases global mRNA N6-methyladenosine (m6A) and 5-methylcytosine (m5C) levels, suggesting an antagonistic relationship between {Psi} and these modifications. Our study underscores the potential of nanopore direct RNA sequencing in revealing the co-regulation of RNA modifications and the capacity of NanoPsiPy in analyzing pseudouridylation and its impact on other RNA modifications.

cancer biology↗

bioRxiv2024

Inhibition of FOXM1 synergizes with BCL2 inhibitor Venetoclax in killing non-t(11;14) multiple myeloma cells via repressing MYC pathway

Despite significant improvements in the prognosis of Multiple Myeloma (MM), relapsed/refractory MM remains a major challenge. BCL2 inhibitor Venetoclax induced complete or very good partial responses in 6% of non-t(11;14) MM cases, compared to 27% in t(11;14) cases, when used as monotherapy in relapsed/refractory MM. Though Venetoclax was proposed to treat t(11;14) cases, the resistance became a concern. Furthermore, non-t(11;14) cases account for 80-85% of MM cases, which underscores the value of Venetoclax in non-t(11;14) MM. Here, we report a recently-invented small molecule inhibitor of FOXM1 NB73 synergizing with Venetoclax in killing MM cells. FOXM1, a critical forkhead box transcription factor in high-risk and relapsed/refractory MM, represents a promising therapeutic target of MM. We examined the mechanisms underlying the synergies of Venetoclax and NB73 using multi-omics and molecular and cellular biology tools in non-t(11;14) myeloma cell lines with high FOXM1 expression. NB73 induces immediate loss of FOXM1, decreases BCL2 expression, and increases Puma expression in myeloma cells. Venetoclax enhances NB73-induced FOXM1 ubiquitination and degradation. The NB73-Venetoclax combination abrogates the binding of FOXM1 to the promoters of genes in the MYC pathway, such as PLK1, MYC, CDC20, and CCNA2, leading to the repression of the transcription of these MYC pathway genes. The PLK1-specific inhibitor GSK461364 synergies with NB73 in suppressing myeloma cell growth. Therefore, NB73 synergizes with Venetoclax in killing myeloma cells. Conclusively, the NB73-Venetoclax combination abolishes FOXM1-mediated transcriptional activation of the MYC pathway, resulting in intensive apoptosis of myeloma cells without t(11;14) but with high FOXM1 expression. Statement of significanceThis study implicates that targeting FOXM1 will alleviate resistance to BCL2 inhibitor Venetoclax in non-t(11;14) myeloma cells expressing high FOXM1.

cancer biology↗