RESUMO
Cyclin-dependent kinase 9 (CDK9) coordinates signaling events that regulate RNA polymerase II (Pol II) pause-release states. It is an important co-factor for transcription factors, such as MYC, that drive aberrant cell proliferation when their expression is deregulated. CDK9 modulation offers an approach for attenuating dysregulation in such transcriptional programs. As a result, numerous drug development campaigns to inhibit CDK9 kinase activity have been pursued. More recently, targeted degradation has emerged as an attractive approach. However, comprehensive evaluation of degradation versus inhibition is still critically needed to assess the biological contexts in which degradation might offer superior therapeutic benefits. We validated that CDK9 inhibition triggers a compensatory mechanism that dampens its effect on MYC expression and found that this feedback mechanism was absent when the kinase is degraded. Importantly, CDK9 degradation is more effective than its inhibition for disrupting MYC transcriptional regulatory circuitry likely through the abrogation of both enzymatic and scaffolding functions of CDK9. Highlights: - KI-CDK9d-32 is a highly potent and selective CDK9 degrader. - KI-CDK9d-32 leads to rapid downregulation of MYC protein and mRNA transcripts levels. - KI-CDK9d-32 represses canonical MYC pathways and leads to a destabilization of nucleolar homeostasis. - Multidrug resistance ABCB1 gene emerged as the strongest resistance marker for the CDK9 PROTAC degrader.
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Three classes of BCMA-directed therapy (BDT) exist: antibody drug-conjugates (ADCs), CAR-T, and T-cell engagers (TCEs), each with distinct strengths and weaknesses. To aid clinicians in selecting between BDTs, we reviewed myeloma patients treated at Mayo Clinic with commercial or investigational BDT between 2018-2023. We identified 339 individuals (1-exposure = 297, 2-exposures = 38, 3-exposures = 4) who received 385 BDTs (ADC = 59, TCE = 134, CAR-T = 192), with median follow-up of 21-months. ADC recipients were older, with more lines of therapy (LOT), and penta-refractory disease. Compared to ADCs, CAR-T (aHR = 0.29, 95%CI = 0.20-0.43) and TCEs (aHR = 0.62, 95%CI = 0.43-0.91) had better progression-free survival (PFS) on analysis adjusted for age, the presence of extramedullary (EMD), penta-refractory disease, multi-hit high-risk cytogenetics, prior BDT, and the number of LOT in the preceding 1-year. Likewise, compared to ADCs, CAR-T (aHR = 0.28, 95%CI = 0.18-0.44) and TCEs (aHR = 0.60, 95%CI = 0.39-0.93) had superior overall survival. Prior BDT exposure negatively impacted all classes but was most striking in CAR-T, ORR 86% vs. 50% and median PFS 13-months vs. 3-months. Of relapses, 54% were extramedullary in nature, and a quarter of these cases had no history of EMD. CAR-T demonstrates superior efficacy and where feasible, should be the initial BDT. However, for patients with prior BDT or rapidly progressive disease, an alternative approach may be preferable.
Assuntos
Antígeno de Maturação de Linfócitos B , Mieloma Múltiplo , Humanos , Mieloma Múltiplo/terapia , Mieloma Múltiplo/mortalidade , Mieloma Múltiplo/tratamento farmacológico , Antígeno de Maturação de Linfócitos B/antagonistas & inibidores , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Imunoterapia Adotiva , Adulto , Imunoconjugados/uso terapêutico , Idoso de 80 Anos ou mais , Recidiva Local de Neoplasia/terapia , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva , Estudos RetrospectivosRESUMO
Transcription factors (TFs) are important mediators of aberrant transcriptional programs in cancer cells. In this study, we focus on TF activity (TFa) as a biomarker for cell-line-selective anti-proliferative effects, in that high TFa predicts sensitivity to loss of function of a given gene (i.e., genetic dependencies [GDs]). Our linear-regression-based framework identifies 3,047 pan-cancer and 3,952 cancer-type-specific candidate TFa-GD associations from cell line data, which are then cross-examined for impact on survival in patient cohorts. One of the most prominent biomarkers is TEAD1 activity, whose associations with its predicted GDs are validated through experimental evidence as proof of concept. Overall, these TFa-GD associations represent an attractive resource for identifying innovative, biomarker-driven hypotheses for drug discovery programs in oncology.
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Neoplasias , Fatores de Transcrição , Humanos , Fatores de Transcrição/metabolismo , Fatores de Transcrição/genética , Neoplasias/genética , Neoplasias/metabolismo , Neoplasias/patologia , Linhagem Celular Tumoral , Fatores de Transcrição de Domínio TEA/metabolismo , Regulação Neoplásica da Expressão Gênica , Proteínas de Ligação a DNA/metabolismo , Proteínas de Ligação a DNA/genética , Biomarcadores Tumorais/metabolismo , Biomarcadores Tumorais/genética , Proliferação de CélulasRESUMO
Aberrant DNA repair is a hallmark of cancer, and many tumors display reduced DNA repair capacities that sensitize them to genotoxins. Here, we demonstrate that the differential DNA repair capacities of healthy and transformed tissue may be exploited to obtain highly selective chemotherapies. We show that the novel N3-(2-fluoroethyl)imidazotetrazine "KL-50" is a selective toxin toward tumors that lack the DNA repair protein O6-methylguanine-DNA-methyltransferase (MGMT), which reverses the formation of O6-alkylguanine lesions. We establish that KL-50 generates DNA interstrand cross-links (ICLs) by a multistep process comprising DNA alkylation to generate an O6-(2-fluoroethyl)guanine (O6FEtG) lesion, slow unimolecular displacement of fluoride to form an N1,O6-ethanoguanine (N1,O6EtG) intermediate, and ring-opening by the adjacent cytidine. The slow rate of N1,O6EtG formation allows healthy cells expressing MGMT to reverse the initial O6FEtG lesion before it evolves to N1,O6EtG, thereby suppressing the formation of toxic DNA-MGMT cross-links and reducing the amount of DNA ICLs generated in healthy cells. In contrast, O6-(2-chloroethyl)guanine lesions produced by agents such as lomustine and the N3-(2-chloroethyl)imidazotetrazine mitozolomide rapidly evolve to N1,O6EtG, resulting in the formation of DNA-MGMT cross-links and DNA ICLs in healthy tissue. These studies suggest that careful consideration of the rates of chemical DNA modification and biochemical DNA repair may lead to the identification of other tumor-specific genotoxic agents.
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Neoplasias Encefálicas , Resistencia a Medicamentos Antineoplásicos , Humanos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/patologia , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Reparo do DNA/efeitos dos fármacos , O(6)-Metilguanina-DNA Metiltransferase/metabolismo , O(6)-Metilguanina-DNA Metiltransferase/antagonistas & inibidores , Imidazóis/química , Imidazóis/farmacologia , Imidazóis/uso terapêuticoRESUMO
Many shark populations are in decline around the world, with severe ecological and economic consequences. Fisheries management and marine protected areas (MPAs) have both been heralded as solutions. However, the effectiveness of MPAs alone is questionable, particularly for globally threatened sharks and rays ('elasmobranchs'), with little known about how fisheries management and MPAs interact to conserve these species. Here we use a dedicated global survey of coral reef elasmobranchs to assess 66 fully protected areas embedded within a range of fisheries management regimes across 36 countries. We show that conservation benefits were primarily for reef-associated sharks, which were twice as abundant in fully protected areas compared with areas open to fishing. Conservation benefits were greatest in large protected areas that incorporate distinct reefs. However, the same benefits were not evident for rays or wide-ranging sharks that are both economically and ecologically important while also threatened with extinction. We show that conservation benefits from fully protected areas are close to doubled when embedded within areas of effective fisheries management, highlighting the importance of a mixed management approach of both effective fisheries management and well-designed fully protected areas to conserve tropical elasmobranch assemblages globally.
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Conservação dos Recursos Naturais , Recifes de Corais , Pesqueiros , Tubarões , Rajidae , Animais , Conservação dos Recursos Naturais/métodosRESUMO
Canid species are highly adaptable, including to urban and peri-urban areas, where they can come into close contact with people. Understanding the mechanisms of wild canid population persistence in these areas is key to managing any negative impacts. The resource dispersion hypothesis predicts that animal density increases and home range size decreases as resource concentration increases, and may help to explain how canids are distributed in environments with an urban-natural gradient. In Australia, dingoes have adapted to human presence, sometimes living in close proximity to towns. Using a targeted camera trap survey and spatial capture-recapture models, we estimated spatial variation in the population density and detection rates of dingoes on Worimi Country in the Great Lakes region of the NSW coast. We tested whether dingo home range and population densities varied across a gradient of human population density, in a mixed-use landscape including, urban, peri-urban, and National Park environs. We found human population density to be a strong driver of dingo density (ranging from 0.025 to 0.433 dingoes/km2 across the natural-urban gradient), and to have a negative effect on dingo home range size. The spatial scale parameter changed depending on survey period, being smaller in the peak tourism period, when human population increases in the area, than in adjacent survey periods, potentially indicating reduced home range size when additional resources are available. Our study highlights the potential value of managing anthropogenic resource availability to manage carnivore densities and potential risk of human-carnivore interactions.
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Despite significant improvement in the outcomes of patients with newly diagnosed multiple myeloma (NDMM) with novel therapies, there is still an underserved high-risk (HR) population that experiences early disease progression and death. With the median survival crossing 10 years, we defined ultrahigh-risk (uHR)MM as MM leading to death within 24-36 months of diagnosis and HRMM as MM leading to death within 36-60 months. Several features have emerged as markers of uHRMM: the co-occurrence of two or more high-risk cytogenetic abnormalities, extramedullary disease, plasma cell leukemia and a high-risk gene expression profiling signature. The heterogeneous risk definition across trials, the few trials available designed for HR patients, and the small HR subgroups in all-comers trials make it difficult to generate recommendations with high levels of evidence. Nevertheless, regardless of treatment administered, several studies consistently showed that achieving and maintaining measurable residual disease negativity is now considered the main factor able to mitigate the adverse prognosis related to baseline features. For fit patients with HR transplant-eligible (TE) NDMM, quadruplet induction/consolidation treatment with anti-CD38 monoclonal antibodies, immunomodulatory agents, proteasome inhibitors and dexamethasone, and autologous stem-cell transplant and maintenance with, if available, at least a doublet combination could be considered the option of choice. For non-TE NDMM, considering the recent data generated and carefully reviewing those upcoming, quadruplet treatment consisting of anti-CD38 monoclonal antibodies, immunomodulatory agents, proteasome inhibitors, and dexamethasone should also be considered. Future trials integrating BCMA-directed novel generation immunotherapies hold great potential for further advancing the treatment landscape in all NDMM patients with HR disease.
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Mieloma Múltiplo , Humanos , Mieloma Múltiplo/terapia , Prognóstico , Fatores de Risco , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Medição de RiscoRESUMO
Multiple myeloma (MM) exhibits significant heterogeneity in its presentation, genetics, and treatment response. Despite therapeutic advances, some patients continue to relapse early (ER, <18-months) and rapidly cycle through therapies. Myriad prognostic factors have been identified and incorporated into risk stratification models; however, these produce discordant, often three-tiered outputs that fail to identify many patients destined for ER. Treatment strategies are increasingly focused on disease biology and trials enriched for high-risk (HR)MM, but consensus on the minimum required testing and a succinct, specific, and clinically meaningful definition for HRMM remains elusive. We review the risk-factors, definitions, and future directions for HRMM.
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Imunoterapia , Mieloma Múltiplo , Mieloma Múltiplo/genética , Mieloma Múltiplo/terapia , Mieloma Múltiplo/diagnóstico , Humanos , Fatores de Risco , PrognósticoRESUMO
RAS oncogenes (collectively NRAS, HRAS and especially KRAS) are among the most frequently mutated genes in cancer, with common driver mutations occurring at codons 12, 13 and 611. Small molecule inhibitors of the KRAS(G12C) oncoprotein have demonstrated clinical efficacy in patients with multiple cancer types and have led to regulatory approvals for the treatment of non-small cell lung cancer2,3. Nevertheless, KRASG12C mutations account for only around 15% of KRAS-mutated cancers4,5, and there are no approved KRAS inhibitors for the majority of patients with tumours containing other common KRAS mutations. Here we describe RMC-7977, a reversible, tri-complex RAS inhibitor with broad-spectrum activity for the active state of both mutant and wild-type KRAS, NRAS and HRAS variants (a RAS(ON) multi-selective inhibitor). Preclinically, RMC-7977 demonstrated potent activity against RAS-addicted tumours carrying various RAS genotypes, particularly against cancer models with KRAS codon 12 mutations (KRASG12X). Treatment with RMC-7977 led to tumour regression and was well tolerated in diverse RAS-addicted preclinical cancer models. Additionally, RMC-7977 inhibited the growth of KRASG12C cancer models that are resistant to KRAS(G12C) inhibitors owing to restoration of RAS pathway signalling. Thus, RAS(ON) multi-selective inhibitors can target multiple oncogenic and wild-type RAS isoforms and have the potential to treat a wide range of RAS-addicted cancers with high unmet clinical need. A related RAS(ON) multi-selective inhibitor, RMC-6236, is currently under clinical evaluation in patients with KRAS-mutant solid tumours (ClinicalTrials.gov identifier: NCT05379985).
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Antineoplásicos , Mutação , Neoplasias , Proteína Oncogênica p21(ras) , Proteínas Proto-Oncogênicas p21(ras) , Animais , Humanos , Camundongos , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Guanosina Trifosfato/metabolismo , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Neoplasias/tratamento farmacológico , Neoplasias/genética , Neoplasias/patologia , Proteína Oncogênica p21(ras)/antagonistas & inibidores , Proteína Oncogênica p21(ras)/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Proteínas Proto-Oncogênicas p21(ras)/antagonistas & inibidores , Transdução de Sinais/efeitos dos fármacos , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Broad-spectrum RAS inhibition has the potential to benefit roughly a quarter of human patients with cancer whose tumours are driven by RAS mutations1,2. RMC-7977 is a highly selective inhibitor of the active GTP-bound forms of KRAS, HRAS and NRAS, with affinity for both mutant and wild-type variants3. More than 90% of cases of human pancreatic ductal adenocarcinoma (PDAC) are driven by activating mutations in KRAS4. Here we assessed the therapeutic potential of RMC-7977 in a comprehensive range of PDAC models. We observed broad and pronounced anti-tumour activity across models following direct RAS inhibition at exposures that were well-tolerated in vivo. Pharmacological analyses revealed divergent responses to RMC-7977 in tumour versus normal tissues. Treated tumours exhibited waves of apoptosis along with sustained proliferative arrest, whereas normal tissues underwent only transient decreases in proliferation, with no evidence of apoptosis. In the autochthonous KPC mouse model, RMC-7977 treatment resulted in a profound extension of survival followed by on-treatment relapse. Analysis of relapsed tumours identified Myc copy number gain as a prevalent candidate resistance mechanism, which could be overcome by combinatorial TEAD inhibition in vitro. Together, these data establish a strong preclinical rationale for the use of broad-spectrum RAS-GTP inhibition in the setting of PDAC and identify a promising candidate combination therapeutic regimen to overcome monotherapy resistance.
Assuntos
Antineoplásicos , Carcinoma Ductal Pancreático , Guanosina Trifosfato , Neoplasias Pancreáticas , Proteínas Proto-Oncogênicas p21(ras) , Animais , Feminino , Humanos , Camundongos , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Apoptose/efeitos dos fármacos , Carcinoma Ductal Pancreático/tratamento farmacológico , Carcinoma Ductal Pancreático/patologia , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Modelos Animais de Doenças , Variações do Número de Cópias de DNA , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Genes myc , Guanosina Trifosfato/metabolismo , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/genética , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/patologia , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/metabolismo , Proteínas Proto-Oncogênicas p21(ras)/genética , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Proteínas Proto-Oncogênicas p21(ras)/antagonistas & inibidores , Resultado do Tratamento , Ensaios Antitumorais Modelo de Xenoenxerto , MutaçãoRESUMO
Chemical discovery efforts commonly target individual protein domains. Many proteins, including the EP300/CBP histone acetyltransferases (HATs), contain several targetable domains. EP300/CBP are critical gene-regulatory targets in cancer, with existing high potency inhibitors of either the catalytic HAT domain or protein-binding bromodomain (BRD). A domain-specific inhibitory approach to multidomain-containing proteins may identify exceptional-responding tumor types, thereby expanding a therapeutic index. Here, we discover that targeting EP300/CBP using the domain-specific inhibitors, A485 (HAT) or CCS1477 (BRD) have different effects in select tumor types. Group 3 medulloblastoma (G3MB) cells are especially sensitive to BRD, compared with HAT inhibition. Structurally, these effects are mediated by the difluorophenyl group in the catalytic core of CCS1477. Mechanistically, bromodomain inhibition causes rapid disruption of genetic dependency networks that are required for G3MB growth. These studies provide a domain-specific structural foundation for drug discovery efforts targeting EP300/CBP and identify a selective role for the EP300/CBP bromodomain in maintaining genetic dependency networks in G3MB.
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Proteína p300 Associada a E1A , Redes Reguladoras de Genes , Meduloblastoma , Humanos , Meduloblastoma/genética , Meduloblastoma/tratamento farmacológico , Meduloblastoma/metabolismo , Meduloblastoma/patologia , Proteína p300 Associada a E1A/metabolismo , Proteína p300 Associada a E1A/genética , Proteína p300 Associada a E1A/antagonistas & inibidores , Linhagem Celular Tumoral , Redes Reguladoras de Genes/efeitos dos fármacos , Animais , Domínios Proteicos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Camundongos , Neoplasias Cerebelares/genética , Neoplasias Cerebelares/tratamento farmacológico , Neoplasias Cerebelares/metabolismo , Neoplasias Cerebelares/patologia , Antineoplásicos/farmacologiaRESUMO
Medulloblastoma is one of the most common malignant brain tumors of children, and 30% of medulloblastomas are driven by gain-of-function genetic lesions in the Sonic Hedgehog (SHH) signaling pathway. EYA1, a haloacid dehalogenase phosphatase and transcription factor, is critical for tumorigenesis and proliferation of SHH medulloblastoma (SHH-MB). Benzarone and benzbromarone have been identified as allosteric inhibitors of EYA proteins. Using benzarone as a point of departure, we developed a panel of 35 derivatives and tested them in SHH-MB. Among these compounds, DS-1-38 functioned as an EYA antagonist and opposed SHH signaling. DS-1-38 inhibited SHH-MB growth in vitro and in vivo, showed excellent brain penetrance, and increased the lifespan of genetically engineered mice predisposed to fatal SHH-MB. These data suggest that EYA inhibitors represent promising therapies for pediatric SHH-MB. SIGNIFICANCE: Development of a benzarone derivative that inhibits EYA1 and impedes the growth of SHH medulloblastoma provides an avenue for improving treatment of this malignant pediatric brain cancer.
Assuntos
Benzobromarona/análogos & derivados , Neoplasias Encefálicas , Neoplasias Cerebelares , Meduloblastoma , Animais , Camundongos , Humanos , Criança , Proteínas Hedgehog , Meduloblastoma/tratamento farmacológico , Meduloblastoma/genética , Neoplasias Cerebelares/tratamento farmacológicoRESUMO
Ubiquitin is a small, highly conserved protein that acts as a posttranslational modification in eukaryotes. Ubiquitination of proteins frequently serves as a degradation signal, marking them for disposal by the proteasome. Here, we report a novel small molecule from a diversity-oriented synthesis library, BRD1732, that is directly ubiquitinated in cells, resulting in dramatic accumulation of inactive ubiquitin monomers and polyubiquitin chains causing broad inhibition of the ubiquitin-proteasome system. Ubiquitination of BRD1732 and its associated cytotoxicity are stereospecific and dependent upon two homologous E3 ubiquitin ligases, RNF19A and RNF19B. Our finding opens the possibility for indirect ubiquitination of a target through a ubiquitinated bifunctional small molecule, and more broadly raises the potential for posttranslational modification in trans.
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To address the dearth of therapeutic options available for relapsed-refractory multiple myeloma (RRMM), attention has shifted to immunotherapeutic strategies, with most products in development targeting the B-cell maturation antigen (BCMA). BCMA is a transmembrane receptor of the tumor necrosis factor receptor superfamily, essential for plasma cell survival and minimally expressed on non-hematopoietic tissues; it represents an ideal therapeutic target. Three categories of BCMA-directed therapies exist, with distinct strengths and weaknesses. Antibody-drug conjugates (ADCs) are immediately available with modest single-agent efficacy in RRMM, but deliverability is hampered by corneal toxicity. CAR T-cells are the most effective class but face significant logistical and financial barriers. Bispecific antibodies offer superior efficacy and tolerability compared to ADCs, but prolonged exposure causes significant cumulative infectious risk. In this review, we will examine the role of BCMA in MM biology, the approved and emerging therapies targeting this antigen, and how these agents can be optimally sequenced.
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Imunoconjugados , Mieloma Múltiplo , Humanos , Mieloma Múltiplo/tratamento farmacológico , Antígeno de Maturação de Linfócitos B , Imunoterapia Adotiva , Imunoconjugados/efeitos adversosRESUMO
Pain is the hallmark symptom causing morbidity for people with sickle cell disease (SCD) and may present as nociceptive, neuropathic, or mixed type pain. Neuropathic pain (NP) is underrecognized and undertreated in patients with SCD and is associated with decreased patient-reported quality of life. Surveys were completed by clinicians caring for adolescents with SCD in the outpatient setting. SCD patients ages 1418 at increased risk of NP completed a patient-facing survey at a scheduled clinic visit. Ninety-four percent of responding clinicians agreed that NP significantly contributes to reported pain in SCD. Clinicians believed that NP medications are effective for reducing chronic pain (62%) and decreasing opioid utilization (44%). Clinician-identified barriers to prescribing NP medications included concerns about medication adherence (82%), lack of pediatric guidelines for NP medications (70%), and perceived patient concern about side effects (65%). More than 1/3 (35%) of clinicians reported that they were not comfortable managing NP medications. Clinician-identified barriers to referral to a pain management specialist included scheduling concerns (88%) and perceived patient/family lack of interest (77%). Most patients expressed willingness to take a medication for NP (78%), see a pain management specialist (84%), or learn more about nonpharmacologic interventions (72%), although most (51%) also reported some concerns about taking a medication for NP, citing insufficient knowledge (34%), and potential for side effects (32%). A minority of respondents (15%) worried about referral to a pain management specialist. Clinician and patient perspectives provide insights that may guide education efforts or other interventions to improve treatment of SCD-related NP.
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Citron kinase (CITK) is an AGC-family serine/threonine kinase that regulates cytokinesis. Despite knockdown experiments implicating CITK as an anticancer target, no selective CITK inhibitors exist. We transformed a previously reported kinase inhibitor with weak off-target CITK activity into a first-in-class CITK chemical probe, C3TD879. C3TD879 is a Type I kinase inhibitor which potently inhibits CITK catalytic activity (biochemical IC50 = 12 nM), binds directly to full-length human CITK in cells (NanoBRET Kd < 10 nM), and demonstrates favorable DMPK properties for in vivo evaluation. We engineered exquisite selectivity for CITK (>17-fold versus 373 other human kinases), making C3TD879 the first chemical probe suitable for interrogating the complex biology of CITK. Our small-molecule CITK inhibitors could not phenocopy the effects of CITK knockdown in cell proliferation, cell cycle progression, or cytokinesis assays, providing preliminary evidence that the structural roles of CITK may be more important than its kinase activity.
Assuntos
Citocinese , Proteínas Serina-Treonina Quinases , Humanos , Proteínas Serina-Treonina Quinases/metabolismo , Divisão Celular , Citocinese/fisiologia , Fosforilação , Proliferação de CélulasRESUMO
Infectious diarrhoea is common post-allogeneic haematopoietic stem-cell transplantation (alloHSCT). While the epidemiology of Clostridioides difficile infection (CDI) post-alloHSCT has been described, the impact of other diarrhoeal pathogens is uncertain. We reviewed all alloHSCT between 2017 and 2022 at a single large transplant centre; 374 patients were identified and included. The 1-year incidence of infectious diarrhoea was 23%, divided into viral (13/374, 3%), CDI (65/374, 17%) and other bacterial infections (16/374, 4%). There was a significant association between infectious diarrhoea within 1 year post-transplant and the occurrence of severe acute lower gastrointestinal graft-versus-host disease (GVHD, OR = 4.64, 95% CI 2.57-8.38, p < 0.001) and inferior GVHD-free, relapse-free survival on analysis adjusted for age, donor type, stem cell source and T-cell depletion (aHR = 1.64, 95% CI = 1.18-2.27, p = 0.003). When the classes of infectious diarrhoea were compared to no infection, bacterial (OR = 6.38, 95% CI 1.90-21.40, p = 0.003), CDI (OR = 3.80, 95% CI 1.91-7.53, p < 0.001) and multiple infections (OR = 11.16, 95% CI 2.84-43.92, p < 0.001) were all independently associated with a higher risk of severe GI GVHD. Conversely, viral infections were not (OR = 2.98, 95% CI 0.57-15.43, p = 0.20). Non-viral infectious diarrhoea is significantly associated with the development of GVHD. Research to examine whether the prevention of infectious diarrhoea via infection control measures or modulation of the microbiome reduces the incidence of GVHD is needed.
Assuntos
Infecções por Clostridium , Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Humanos , Transplante Homólogo/efeitos adversos , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Doença Enxerto-Hospedeiro/epidemiologia , Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/prevenção & controle , Infecções por Clostridium/etiologia , Diarreia/epidemiologia , Diarreia/etiologia , Estudos RetrospectivosRESUMO
The histone lysine demethylases KDM4A-C are involved in physiologic processes including stem cell identity and self-renewal during development, DNA damage repair, and cell-cycle progression. KDM4A-C are overexpressed and associated with malignant cell behavior in multiple human cancers and are therefore potential therapeutic targets. Given the role of KDM4A-C in development and cancer, we aimed to test the potent, selective KDM4A-C inhibitor QC6352 on oncogenic cells of renal embryonic lineage. The anaplastic Wilms tumor cell line WiT49 and the tumor-forming human embryonic kidney cell line HEK293 demonstrated low nanomolar QC6352 sensitivity. The cytostatic response to QC6352 in WiT49 and HEK293 cells was marked by induction of DNA damage, a DNA repair-associated protein checkpoint response, S-phase cell-cycle arrest, profound reduction of ribosomal protein gene and rRNA transcription, and blockade of newly synthesized proteins. QC6352 caused reduction of KDM4A-C levels by a proteasome-associated mechanism. The cellular phenotype caused by QC6352 treatment of reduced migration, proliferation, tumor spheroid growth, DNA damage, and S-phase cell-cycle arrest was most closely mirrored by knockdown of KDM4A as determined by siRNA knockdown of KDM4A-C. QC6352 sensitivity correlated with high basal levels of ribosomal gene transcription in more than 900 human cancer cell lines. Targeting KDM4A may be of future therapeutic interest in oncogenic cells of embryonic renal lineage or cells with high basal expression of ribosomal protein genes.
Assuntos
Compostos Heterocíclicos de 4 ou mais Anéis , Histona Desmetilases com o Domínio Jumonji , Proteínas Ribossômicas , Humanos , Células HEK293 , Histona Desmetilases com o Domínio Jumonji/genética , Linhagem Celular Tumoral , Rim/metabolismo , Ribossomos/metabolismoRESUMO
Chromosomal instability (CIN) is a hallmark of cancer, caused by persistent errors in chromosome segregation during mitosis. Aggressive cancers like high-grade serous ovarian cancer (HGSOC) and triple-negative breast cancer (TNBC) have a high frequency of CIN and TP53 mutations. Here, we show that inhibitors of the KIF18A motor protein activate the mitotic checkpoint and selectively kill chromosomally unstable cancer cells. Sensitivity to KIF18A inhibition is enriched in TP53-mutant HGSOC and TNBC cell lines with CIN features, including in a subset of CCNE1-amplified, CDK4-CDK6-inhibitor-resistant and BRCA1-altered cell line models. Our KIF18A inhibitors have minimal detrimental effects on human bone marrow cells in culture, distinct from other anti-mitotic agents. In mice, inhibition of KIF18A leads to robust anti-cancer effects with tumor regression observed in human HGSOC and TNBC models at well-tolerated doses. Collectively, our results provide a rational therapeutic strategy for selective targeting of CIN cancers via KIF18A inhibition.