Systematic Kinase Inhibitor Profiling Identifies CDK9 as a Synthetic Lethal Target in NUT Midline Carcinoma

<div>Abstract<p>NUT midline carcinoma (NMC) is an aggressive subtype of squamous cell carcinoma that typically harbors BRD4/3–NUT fusion oncoproteins that block differentiation and maintain tumor growth. In 20% of cases, <i>NUT</i> is fused to uncharacterized non-<i>BRD</i> gene(s). We established a new patient-derived NMC cell line (1221) and demonstrated that it harbors a novel <i>NSD3–NUT</i> fusion oncogene. We find that NSD3–NUT is both necessary and sufficient for the blockade of differentiation and maintenance of proliferation in NMC cells. NSD3–NUT binds to BRD4, and BRD bromodomain inhibitors induce differentiation and arrest proliferation of 1221 cells. We find further that NSD3 is required for the blockade of differentiation in BRD4–NUT-expressing NMCs. These findings identify NSD3 as a novel critical oncogenic component and potential therapeutic target in NMC.</p><p><b>Significance:</b> The existence of a family of fusion oncogenes in squamous cell carcinoma is unprecedented, and should lead to key insights into aberrant differentiation in NMC and possibly other squamous cell carcinomas. The involvement of the NSD3 methyltransferase as a component of the NUT fusion protein oncogenic complex identifies a new potential therapeutic target. <i>Cancer Discov; 4(8); 928–41. ©2014 AACR</i>.</p><p>This article is highlighted in the In This Issue feature, p. 855</p></div>

Background: NUT midline carcinoma (NMC) is an aggressive subtype of poorly differentiated squamous cell carcinoma, occurring anywhere along the trunk or the head, most commonly along the midline. NMC is characterized by chromosomal translocation resulting in the fusion of the gene nuclear protein in testis (NUT) and bromodomain and extraterminal domain (BET) proteins (BRD2,3,4 and BRDT). The acquired bromodomain region tethers the BRD-NUT fusion protein to acetylated chromatin. The molecular mechanism by which BRD-NUT is involved in the generation of NMC is unclear, although it seems to be related to massive disruption of normal gene regulation at key cell type–specific genes. After binding to acetylated chromatin through bromodomains, the NUT moiety of the fusion protein strongly interacts with and recruits E1A interacting protein of 300 kDa (EP300/P300), initiating cycles of BRD-NUT/P300 recruitment and creating chromatin “megadomains” enriched in histone H3 lysine 27 acetylation (H3K27ac), a specific enhancer and super-enhancer histone mark. The creation of these domains activates transcription of adjacent genes that seem to be critical for the progression of NMC. As BET inhibitors have shown activity in NMC and P300 is important in its pathophysiology, we examined the pre-clinical activity of NEO2734 and NEO1132, novel dual BET and P300/CBP inhibitors (Giles et al Abs #2510 ESMO 2018), in NMC. Results:Considering the important roles of BET proteins and P300 in NMC, two NMC-cell lines (1015 and 14169, C. French: Brigham and Women’s Hospital) were treated with dual BET and P300/CBP inhibitors NEO2734 and NEO1131 (Epigene Therapeutics Inc), BET inhibitors JQ1 and iBET155 (GSK525762) (Sigma-Aldrich) and P300/CBP inhibitor CPI-637 (MedChem Express) for comparison. The average IC50 values of the two molecules were 44.04 nM and 130.73 nM respectively in 1015 cell line and 77.37 nM and 123.95 nM in 14169 cell line. For the two cell lines, the dual inhibitor NEO2734 was more potent than NEO1131, IBET155 and p300 inhibitors. The 14169 cell line, with a higher number of genetic lesions than the 1015 cell line, was more resistant to NEO2734 than the 1015 cell line. Conclusions: The dual inhibitor NEO2734 showed superior in vitroanti-proliferative activity in two NMC cell lines compared with single BET and p300 inhibitors. We also observed the presence of two different cell populations (adherent and suspension cells) in both NMC cell lines with adherent cells being more resistant to NEO2734, Differences in the responses to NEO2734 in NMC are being studied to molecularly identify biomarkers of resistance. These data support the inclusion of patients with NMC in clinical studies of NEO2734. Citation Format: Tian Tian, Marc Cosín, Francis Giles, Irene Braña, Elena Garralda, Sandra Peiró. NEO2734, a novel dual BET and P300/CBP bromodomain inhibitor, is more active in NUT midline carcinoma than single agent BET or P300/CBP inhibitors [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr B008. doi:10.1158/1535-7163.TARG-19-B008

NUT midline carcinoma (NMC) is a rare but highly aggressive cancer typically caused by the translocation t(15;19), which results in the formation of the BRD4-NUT fusion oncoprotein. Previous studies have demonstrated that fusion of the NUT protein with the double bromodomains of BRD4 may significantly alter the cellular gene expression profile to contribute to NMC tumorigenesis. However, the mechanistic details of this BRD4-NUT function remain poorly understood. In this study, we examined the NUT function in transcriptional regulation by targeting it to a LacO transgene array integrated in U2OS 2-6-3 cells, which allow us to visualize how NUT alters the in situ gene transcription dynamic. Using this system, we demonstrated that the NUT protein tethered to the LacO locus recruits p300/CREB-binding protein (CBP), induces histone hyperacetylation, and enriches BRD4 to the transgene array chromatin foci. We also discovered that, in BRD4-NUT expressed in NMC cells, the NUT moiety of the fusion protein anchored to chromatin by the double bromodomains also stimulates histone hyperacetylation, which causes BRD4 to bind tighter to chromatin. Consequently, multiple BRD4-interacting factors are recruited to the NUT-associated chromatin locus to activate in situ transgene expression. This gene transcription function was repressed by either expression of a dominant negative inhibitor of the p300-NUT interaction or treatment with (+)-JQ1, which dissociates BRD4 from the LacO chromatin locus. Our data support a model in which BRD4-NUT-stimulated histone hyperacetylation recruits additional BRD4 and interacting partners to support transcriptional activation, which underlies the BRD4-NUT oncogenic mechanism in NMC.

NUT midline carcinoma (NMC), a subtype of squamous cell cancer, is one of the most aggressive human solid malignancies known. NMC is driven by the creation of a translocation oncoprotein, BRD4-NUT, which blocks differentiation and drives growth of NMC cells. BRD4-NUT forms distinctive nuclear foci in patient tumors, which we found correlate with ∼100 unprecedented, hyperacetylated expanses of chromatin that reach up to 2 Mb in size. These "megadomains" appear to be the result of aberrant, feed-forward loops of acetylation and binding of acetylated histones that drive transcription of underlying DNA in NMC patient cells and naïve cells induced to express BRD4-NUT. Megadomain locations are typically cell lineage-specific; however, the cMYC and TP63 regions are targeted in all NMCs tested and play functional roles in tumor growth. Megadomains appear to originate from select pre-existing enhancers that progressively broaden but are ultimately delimited by topologically associating domain (TAD) boundaries. Therefore, our findings establish a basis for understanding the powerful role played by large-scale chromatin organization in normal and aberrant lineage-specific gene transcription.

<div>Abstract<p>The antineoplastic, prodifferentiative effects of bromodomain and extra-terminal (BET) bromodomain (BRD) inhibitors were initially discovered in NUT midline carcinoma (NMC), an aggressive subtype of squamous cancer driven by the BRD4–NUT fusion oncoprotein. BRD4–NUT blocks differentiation and maintains tumor growth through a potent chromatin-modifying mechanism. OTX015/MK-8628, a novel oral BET inhibitor, targets BRD2/3/4/T with preclinical activity in NMC and several other tumor types and is currently in clinical development. Antitumor activity was evaluated in four patients with advanced-stage NMC with confirmed <i>BRD4–NUT</i> fusions who were treated with 80 mg OTX015/MK-8628 once daily in a compassionate-use context. Two patients responded rapidly with tumor regression and symptomatic relief, and a third had meaningful disease stabilization with a minor metabolic response. The main side effects were mild to moderate gastrointestinal toxicity and fatigue, and reversible grade 3 thrombocytopenia. This is the first proof-of-concept evidence of clinical activity of a BRD inhibitor in targeting BRD4–NUT.</p><p><b>Significance:</b> We present the first clinical proof-of-concept that targeting BRD4–NUT with a BET inhibitor results in impressive and rapid antitumor activity in NMC. It offers strong potential for future clinical application in this rare patient population as either a single agent or in combination with other agents. <i>Cancer Discov; 6(5); 492–500. ©2016 AACR.</i></p><p>This article is highlighted in the In This Issue feature, p. 461</p></div>

Introduction: Cigarette smoking is an important risk factor for the development pancreatic ductal adenocarcinoma (PDAC). Nicotine and nitrosamines cause pancreatic cell injury and contribute to a cascade of oncogenic events. Among multiple tobacco specific nitrosamines, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) is considered to be the most carcinogenic and induces DNA double strand-breaks (DSBs). However, identification of potential prognostic biomarkers and experimental models of smoking-induced PDAC remain unknown. We have studied phosphorylated histone H2AX (γH2AX), a marker for double-stranded DNA breaks, as a new biomarker for detecting cigarette smoke-induced pathogenesis of PDAC. Experimental Procedure: We have characterized the expression of γH2AX protein in human pancreatic tissues, human pancreatic duct epithelial (HPDE)6, PDAC cell lines, and PanIn, primary PDAC (PDA) and liver metastasis (LMP) cell lines generated from a genetically engineered mice model of PDAC. Kaplan-Meier survival analysis was performed to determine the significance of γH2AX expression amongst smokers and non-smokers with PDAC. HPDE6 and PanIN cells were cultured for 4 days in the presence or absence of cigarette smoke (CS) (0-25μg/ml) or NNK (0-10μM). Cell cycle analysis and apoptosis were assessed through flow cytometry with the markers propidium iodide and annexin V respectively. HPDE6 and PanIN cells treated with CS or NNK for up to 50 days were analyzed for rapid activation of DNA damage response (DDR) pathway proteins γH2AX, RAD51, BRCA1, BRCA2, phospho-CHK2 and phospho-CHK1. Cells were treated with either CS or NNK along with a CHK2 inhibitor and analyzed for activation of γH2AX. To determine DNA integrity, accumulation of γH2AX was measured by ELISA in cells treated with CS or NNK. Immunofluorescence confocal microscopy was utilized to examine the role of γH2AX on nuclear foci formation with DNA repair complexes by quantifying the amount of co-localization. To replicate chronic smoke exposure, we treated HPDE6 and PanIn cells with 1 and 10 µg/ml CS or 10nM and 1µM NNK for 10 passages, and examined these cell lines for DSBs by comet assay, apoptosis markers by protein array and in vitro tumorigenicity by colony formation assay. Results: γH2AX expression was significantly higher (p<0.0001) in smokers when compared to non-smokers. Overall survival of patients with high γH2AX expression in their primary tumor was associated with significantly decreased median survival (11 months) when compared to low γH2AX expression (36 months, p=0.0007). HPDE6 cells exposed to CS or NNK, showed more than 80% survival. The surviving cells had altered morphology, acquired mesenchymal characteristics and displayed increased tumorigenicity suggesting that these cells acquire resistance to apoptosis after CS or NNK exposure. In addition, exposure of cells to CS or NNK resulted in generation of γH2AX and induction of phospho-CHK2 expression. RAD51 and phospho-CHK2 co-localize with γH2AX after DNA damage with CS or NNK exposure. Inhibition of CHK2 reduced expression of γH2AX. The product of the tumor suppressor gene BRCA2 co-localized with γH2AX indicating that γH2AX is necessary for the recruitment of DNA repair factors to the site of DNA damage. BRCA2 mutant cell line CAPAN1 exhibited a substantially reduced ability to form co-localization with RAD51 and γH2AX, consistent with a role of γH2AX in DNA damage repair. Conclusion: This work supports the role of γH2AX as a new molecular biomarker to assess the contribution of cigarette smoking-induced PDAC. γH2AX is necessary for DNA damage repair in PDAC and its activation is dependent on CHK2. Therapies that can block γH2AX expression by inhibiting upstream kinases may be a new potential therapeutic approach to treat and/or prevent PDAC. Citation Format: Kumaraswamy Honnenahally, Chanjuan Shi, Xi Chen, Jason Castellanos, Nipun Merchant, Timothy Blackwell, Nagaraj Nagathihalli. γH2AX: A molecular marker of DNA damage response in smoking-induced pancreatic ductal adenocarcinoma. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Innovations in Research and Treatment; May 18-21, 2014; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2015;75(13 Suppl):Abstract nr A33.

Functional and chemical genomic approaches, such as the Broad Institute’s Cancer Dependency Map and PRISM (Profiling Relative Inhibition Simultaneously in Mixtures) chemical screening, have revolutionized the identification of context-specific genetic dependencies and therapeutic vulnerabilities across diverse cancer types. These datasets empower the identification of therapeutic strategies in cancers with limited actionable mutations. Alveolar rhabdomyosarcoma (aRMS), a pediatric cancer driven by a hard-to-target fusion oncoprotein, PAX3::FOXO1, typically expresses no immediately actionable mutations. Using aRMS as a disease model, we utilized the Broad Institute’s Cancer Dependency Map dataset, coupled with single-sample gene set enrichment analysis (ssGSEA), to systematically assess protein complex dependencies in aRMS. We nominated the Mediator complex and further identified CDK8, a member of the Mediator kinase module, as a clinically actionable target in aRMS. Other members of the Mediator kinase module, including CCNC, MED12, and MED13, are also essential to aRMS proliferation. In addition, in aRMS cell lines, there was a positive correlation (R=0.68) between the CDK8 gene-effect score and the effect of the CDK8 inhibitor, BI-1347, in the PRISM screening. We validated that both genetic loss of CDK8 and kinase inhibition by CDK8 small molecule inhibitors impaired aRMS cell line growth in vitro and induced evidence of myogenic differentiation. Our in vivo studies demonstrated that the clinical grade CDK8 inhibitor SEL-120-34A decreased aRMS cell line xenograft tumor growth. Functional genomic screens also serve as powerful tools to understand the mechanisms of small molecule inhibitors and to identify resistance and sensitizer mechanisms. We thus performed an unbiased genome-scale CRISPR-Cas9 screen with the CDK8 inhibitor BI-1347 in aRMS. We determined that the maximal anti-tumor activity of the CDK8 inhibitor requires the presence of the SAGA complex, particularly the SAGA HAT module. We further identified SIX4 as a key transcription factor mediating CDK8 inhibitor-induced transcriptional activation of myogenic differentiation genes. In addition, we revealed that the maximal activity of BI-1347 requires the presence of the Mediator kinase module, suggesting a trapping-related mechanism in addition to kinase enzymatic inhibition. Accordingly, we found that CDK8 inhibition increased the binding of components of the Mediator kinase module and SIX4 and TADA2B at enhancers of terminal muscle differentiation-related genes, such as VGLL2, SEMA3D, MYL1, leading to their transcriptional activation, as shown by PRO-seq analyses. These findings provide a framework for uncovering therapeutic targets using network-based analysis of functional genomic screens, and for studying the small molecular inhibitor mechanisms. In aRMS, CDK8 inhibition is a differentiation-inducing therapeutic strategy. Citation Format: Susu Zhang, Kathleen Engel, Assil Fahs, Clare Malone, Kenneth Ross, Marissa Just, Brian Guedes, Diyana Granum, Kristianne M Oristian, Alexander Kovach, Gabriela Alexe, Giulia Digiovanni, Leen Barbar, Rex Bentley, Christian Cerda-Smith, Ozgun Le Roux, Elizabeth Mendes, Seth P Zimmerman, Matthew Rees, Jennifer Roth, Jack F Shern, Kris C Wood, Christopher M Counter, Corinne M Linardic, Kimberly Stegmaier. CDK8 Inhibition Releases the Muscle Differentiation Block in Fusion-Driven Alveolar Rhabdomyosarcoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Discovery and Innovation in Pediatric Cancer— From Biology to Breakthrough Therapies; 2025 Sep 25-28; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2025;85(18_Suppl_2):Abstract nr A022-PR005.

Multinucleated retinal pigment epithelium (RPE) cells have been reported in humans and other mammals. Rodents have an extremely high percentage of multinucleated cells (more than 80%). Both mouse and human multinucleated RPE cells exhibit specific regional distributions that are potentially correlated with photoreceptor density. However, detailed investigations of multinucleated RPE in different species and their behavior after DNA damage are missing. Here, we compared the composition of multinucleated RPE cells in nocturnal and diurnal animals that possess distinct rod and cone proportions. We further investigated the reactive oxygen species (ROS) production and DNA damage response in mouse mononucleated and multinucleated RPE cells and determined the effect of p53 dosage on the DNA damage response in these cells. Our results revealed an unrealized association between multinucleated RPE cells and nocturnal vision. In addition, we found multinucleated RPE cells exhibited increased ROS production and DNA damage after X-ray irradiation. Furthermore, haploinsufficiency of p53 led to increased DNA damage frequency after irradiation, and mononucleated RPE cells were more sensitive to a change in p53 dosage. In conclusion, this study provides novel information on in vivo PRE topography and the DNA damage response, which may reflect specific requirements for vision adaption and macular function.

2598 Background: Synthetic lethal targets are proteins that are contextually vulnerable. Inhibitors of PARP1, for example, selectively produce a lethal phenotype in the context of cancer cells which have lost BRCA1 or BRCA2 function. As a high mutation rate is a hallmark of many cancers, targeting synthetic lethal interactions to selectively inhibit cancer cells with altered genetic backgrounds may increase the specificity and efficacy of therapeutics. Recently, clinical trials have targeted synthetic lethal pairs such as EGFR and BRAF, TP53 and BCL2, and PTEN and CHD1. Previous attempts to identify synthetic lethal targets have relied on empirical results from published studies of biological pathways perturbed in cancer cells. Developing strategies to rapidly identify synthetic lethals by combining multiple experimental and computational approaches would result in a new class of potential cancer drug targets beyond the existing efforts that rely on single experimental or computational methods alone. Methods: Here we present Expansive AI, an artificial intelligence augmented knowledge network that enables rapid hypothesis generation for accelerated discovery research. Using a purpose-built, hypergraph database of massive, integrated genomic and biomedical data, we can query all synthetic lethals and their component genes, as well as a wealth of data related to these genes. The database of biological data includes 11,000+ cancer genomes from TCGA, prior knowledge resources such as gene ontology and pathway resources, and experimental data including chemical and protein interaction and patent data. The hypergraph’s architecture allows for linking and nesting data, enabling efficient extraction of biologically-relevant features. Results: Using these features, a neural network classified 540 new candidate pairs that have previously not been reported. The candidate pairs were filtered to include only known oncogenes and least-studied genes. This produced a list of gene pairs which may represent the most novel class of synthetic lethal target candidates identified to date. Conclusions: We highlight the results of this AI-based approach and discuss validation efforts of the predicted interactions in specific cancer contexts.

BackgroundChk1 forms a core component of the DNA damage response and small molecule inhibitors are currently being investigated in the clinic as cytotoxic chemotherapy potentiators. Recent evidence suggests that Chk1 inhibitors may demonstrate significant single agent activity in tumors with specific DNA repair defects, a constitutively activated DNA damage response or oncogene induced replicative stress.MethodsGrowth inhibition induced by the small molecule Chk1 inhibitor V158411 was assessed in a panel of human leukemia and lymphoma cell lines and compared to cancer cell lines derived from solid tumors. The effects on cell cycle and DNA damage response markers were further evaluated.ResultsLeukemia and lymphoma cell lines were identified as particularly sensitive to the Chk1 inhibitor V158411 (mean GI50 0.17 μM) compared to colon (2.8 μM) or lung (6.9 μM) cancer cell lines. Chk1 inhibition by V158411 in the leukemia and lymphoma cell lines induced DNA fragmentation and cell death that was both caspase dependent and independent, and prevented cells undergoing mitosis. An analysis of in vitro pharmacodynamic markers identified a dose dependent decrease in Chk1 and cyclin B1 protein levels and Cdc2 Thr15 phosphorylation along with a concomitant increase in H2AX phosphorylation at Ser139 following V158411 treatment.ConclusionsThese data support the further evaluation of Chk1 inhibitors in hematopoietic cancers as single agents as well as in combination with standard of care cytotoxic drugs.

Radiosynthesis and radiopharmacological evaluation of cyclin-dependent kinase 4 (Cdk4) inhibitors

Recent evidence suggests that the cyclin-dependent kinase (Cdk) inhibitors p27Kip1 and p21Cip1 are important factors in T cell anergy, but it has remained unclear whether anergy can be induced in their absence. We therefore induced anergy by stimulation of purified T cells from wild-type, p21Cip1-/-, and p27Kip1-/- mice with anti-CD3 antibodies. Anergic wild-type T cells were arrested in the G1 phase of the cell cycle with a high p27Kip1 protein level and low Cdk2 activity. In p27-/- and p21-/- T cells, the pattern of protein expression was preserved, but Cdk2 activity was increased. To confirm the in vivo relevance of these data, anergy was induced by repeated injection of mice with staphylococcal enterotoxin B (SEB), which leads to partial deletion of the responsive Vbeta8+ T cell population and anergy in the remaining T cells. p21-/- mice and wild-type mice reacted similarly to this treatment. p27-/- mice showed reduced deletion of SEB-responsive T cells, but persisting T cells were anergic. These data indicate that other cell cycle regulators contribute to the cell cycle arrest of anergic T cells, as neither Cdk inhibitor is required for the induction of anergy.

Introduction: FDA approved CDK4/6 inhibition medicines has demonstrated significant clinical benefits in patients with HR+/HER2- breast cancer. However, the dual CDK4/6 inhibitors also present severe on-target toxicity leading to severe adverse effects (SAE) in the clinic, such as neutropenia. Clinical studies with palbociclib reported grade 3-4 neutropenia events in 60-66% of patients receiving the treatment. To dissect the cause of the clinical toxicity of CDK4/6, it has been found that CDK6, not CDK4, is directly involved in the differentiation of myeloid cell in which CDK6 expression is up-regulated. Thus, we sought to develop a mono-CDK targeting agent, a CDK4 inhibitor, to grant similar pharmacological potency against HR+/HER2- breast cancer while diminishing or even abolishing CDK6 on-target toxicity to improve the efficacy, and more importantly, the safety of the hallmark cell cycle therapies. To this end, we at TYK Medicines have developed lead CDK4 inhibitor candidates (TY-2072) with high selectivity and potency. Results: TY-2072 demonstrates high selectivity against CDK4, and more than 17-fold selectivity against CDK6 compared to palbociclib, proving that TY-2072 is a CDK4 inhibitor rather than a CDK4/6 dual inhibitor. Western blot assays showed a dose-dependent reduction in phosphorylated RB (Ser780) in breast cancer cell lines after 48 hours TY-2072 treatment. The anti-proliferation effects of CDK4 inhibitors were assessed with MCF7 (breast cancer, CDK4 sensitive), JEKO-1 (mantle cell lymphoma), and MOLM13 (acute myeloid leukemia, CDK6 sensitive) through a CTG cell viability assay after 5-day incubation. Palbociclib shows a strong inhibitory effect on MCF7/T47D cells due to dual CDK4 and CDK6 kinase activity. TY-2072 strongly inhibited JEKO-1, but had no inhibitory effect on CDK6 high-expression MOLM13. In MCF7-xenograft mouse model, TY-2072 showed significant suppression of tumor growth in a dose-dependent manner at 20 and 40 mg/kg BID, TY-2072 exhibited synergetic effects with Fulvestrant on anti-tumor growth inhibition with good tolerance, evidenced by the maintenance of body weight of the animals throughout the study. We conducted preliminary in vitro combination studies with lead CDK4 compounds, and the combination of a selective CDK4 inhibitor with a CDK2 inhibitor or a PI3K inhibitor demonstrated a significant synergistic inhibitory effect on MCF7 cells and MCF7 Palbociclib-resistant cells. Positive results were also observed when TY-2072 was combined with AMG510/MRTX849 in the NSCLC H2122 (KRAS G12C) cells. In summary, the optimization of the lead compounds is continuing with goal to identify a PCC compound in the near future for IND-enabling studies. Citation Format: Mei Hua Li, Apeng Liang, Kai Wang, Yi Long, Rui Wu, Hui Xu, Jian Zhu, Guangbin Liu, Ling Fang, Xi Wang, Chenjie Pan, Yiming Cai, Xiang Zhang, Shengli Dong, Yu Yu, Xinlong Yang, Chao Zhou, Wei Wu, Chengshan Niu, Mingyu Jiang, Shaoqing Chen, Jun Li, Yusheng Wu. Development of a novel selective CDK4 inhibitor for HR+/HER2- breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5329.

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