Welcome to Dana-Farber's Research News
April 1, 2023
This twice-monthly newsletter highlights the research endeavors at Dana-Farber Cancer Institute, noting recently published papers available from PubMed where Dana-Farber faculty are listed as first or senior authors. If you are a Dana-Farber faculty member and you think your paper is missing from Research News, please let us know at: Michael_buller@dfci.harvard.edu.
Blood
CDK7 Controls E2F- and MYC-Driven Proliferative and Metabolic Vulnerabilities in Multiple Myeloma
Fong Ng J, Samur MK, Morelli E, Chyra Z, Derebail S, Epstein CB, Kwiatkowski N, Mitsiades CS, Anderson KC, Munshi NC, Fulciniti
Therapeutic targeting of CDK7 has proven beneficial in pre-clinical studies, yet the off-target effects of currently available CDK7 inhibitors make it difficult to pinpoint the exact mechanisms behind MM cell death mediated by CDK7 inhibition. Here, we show that CDK7 expression positively correlates with E2F and MYC transcriptional programs in multiple myeloma (MM) patient cells; and its selective targeting counteracts E2F activity via perturbation of the CDKs/Rb axis and impairs MYC-regulated metabolic gene signatures translating into defects in glycolysis and reduced levels of lactate production in MM cells. CDK7 inhibition using the covalent small molecule inhibitor YKL-5-124 elicits a strong therapeutic response with minimal effects on normal cells, and causes in vivo tumor regression increasing survival in several MM mouse models including a genetically engineered mouse model of MYC-dependent MM. Through its role as a critical cofactor and regulator of MYC and E2F activity, CDK7 is therefore a master regulator of oncogenic cellular programs supporting MM growth and survival, and a valuable therapeutic target providing rationale for development of YKL-5-124 for clinical use.
Cancer Discovery
A Ubiquitination Cascade Regulating the Integrated Stress Response and Survival in Carcinomas
Cervia LD, Shibue T, Borah AA, Gaeta B, He L, Leung L, Li N, Moyer SM, Shim BH, Dumont N, Gonzalez A, Bick NR, Kazachkova M, Dempster JM, Krill-Burger JM, Piccioni F, Udeshi ND, Olive ME, Carr SA, Root DE, McFarland JM, Vazquez F, Hahn WC
Systematic identification of signaling pathways required for the fitness of cancer cells will facilitate the development of new cancer therapies. We used gene essentiality measurements in 1,086 cancer cell lines to identify selective coessentiality modules and found that a ubiquitin ligase complex composed of UBA6, BIRC6, KCMF1, and UBR4 is required for the survival of a subset of epithelial tumors that exhibit a high degree of aneuploidy. Suppressing BIRC6 in cell lines that are dependent on this complex led to a substantial reduction in cell fitness in vitro and potent tumor regression in vivo. Mechanistically, BIRC6 suppression resulted in selective activation of the integrated stress response (ISR) by stabilization of the heme-regulated inhibitor, a direct ubiquitination target of the UBA6/BIRC6/KCMF1/UBR4 complex. These observations uncover a novel ubiquitination cascade that regulates ISR and highlight the potential of ISR activation as a new therapeutic strategy.
SIGNIFICANCE: We describe the identification of a heretofore unrecognized ubiquitin ligase complex that prevents the aberrant activation of the ISR in a subset of cancer cells. This provides a novel insight on the regulation of ISR and exposes a therapeutic opportunity to selectively eliminate these cancer cells. See related commentary Leli and Koumenis, p. 535. This article is highlighted in the In This Issue feature, p. 517.
Cancer Discovery
Discovery of Targets for Immune-Metabolic Antitumor Drugs Identifies Estrogen-Related Receptor Alpha
Sahu A, Wang X, Munson P, Wang X, Gu SS, Qian G, Nicol P, Zeng Z, Wang C, Tokheim C, Zhang W, Fu J, Wang J, Liu JS, Juric D, Meyer CA, Liu XS, Fisher DE, Flaherty KT
Drugs that kill tumors through multiple mechanisms have the potential for broad clinical benefits. Here, we first developed an in silico multiomics approach (BipotentR) to find cancer cell-specific regulators that simultaneously modulate tumor immunity and another oncogenic pathway and then used it to identify 38 candidate immune-metabolic regulators. We show the tumor activities of these regulators stratify patients with melanoma by their response to anti-PD-1 using machine learning and deep neural approaches, which improve the predictive power of current biomarkers. The topmost identified regulator, ESRRA, is activated in immunotherapy-resistant tumors. Its inhibition killed tumors by suppressing energy metabolism and activating two immune mechanisms: (i) cytokine induction, causing proinflammatory macrophage polarization, and (ii) antigen-presentation stimulation, recruiting CD8+ T cells into tumors. We also demonstrate a wide utility of BipotentR by applying it to angiogenesis and growth suppressor evasion pathways. BipotentR (http://bipotentr.dfci.harvard.edu) provides a resource for evaluating patient response and discovering drug targets that act simultaneously through multiple mechanisms.
SIGNIFICANCE: BipotentR presents resources for evaluating patient response and identifying targets for drugs that can kill tumors through multiple mechanisms concurrently. Inhibition of the topmost candidate target killed tumors by suppressing energy metabolism and effects on two immune mechanisms. This article is highlighted in the In This Issue feature, p. 517.
Cancer Discovery
Mutant NPM1 Directly Regulates Oncogenic Transcription in Acute Myeloid Leukemia
Uckelmann HJ, Haarer EL, Takeda R, Wong EM, Hatton C, Marinaccio C, Perner F, Rajput M, Antonissen NJC, Wen Y, Armstrong SA
The dysregulation of developmental and stem cell-associated genes is a common phenomenon during cancer development. Around half of patients with acute myeloid leukemia (AML) express high levels of HOXA cluster genes and MEIS1. Most of these AML cases harbor an NPM1 mutation (NPM1c), which encodes for an oncoprotein mislocalized from the nucleolus to the cytoplasm. How NPM1c expression in hematopoietic cells leads to its characteristic gene-expression pattern remains unclear. Here, we show that NPM1c directly binds to specific chromatin targets, which are co-occupied by the histone methyltransferase KMT2A (MLL1). Targeted degradation of NPM1c leads to a rapid decrease in gene expression and loss of RNA polymerase II, as well as activating histone modifications at its targets. We demonstrate that NPM1c directly regulates oncogenic gene expression in collaboration with the MLL1 complex and define the mechanism by which MLL1-Menin small-molecule inhibitors produce clinical responses in patients with NPM1-mutated AML.
SIGNIFICANCE: We uncovered an important functional role of mutant NPM1 as a crucial direct driver of oncogenic gene expression in AML. NPM1c can bind to chromatin and cooperate with the MLL complex, providing the first functional insight into the mechanism of Menin-MLL inhibition in NPM1c leukemias. See related article by Wang et al., p. 724. This article is highlighted in the In This Issue feature, p. 517.
Cell
Cryo-EM Structure of the RADAR Supramolecular Anti-Phage Defense Complex
Duncan-Lowey B, Johnson AG, Rawson S, Mayer ML, Kranzusch PJ
RADAR is a two-protein bacterial defense system that was reported to defend against phage by "editing" messenger RNA. Here, we determine cryo-EM structures of the RADAR defense complex, revealing RdrA as a heptameric, two-layered AAA+ ATPase and RdrB as a dodecameric, hollow complex with twelve surface-exposed deaminase active sites. RdrA and RdrB join to form a giant assembly up to 10 MDa, with RdrA docked as a funnel over the RdrB active site. Surprisingly, our structures reveal an RdrB active site that targets mononucleotides. We show that RdrB catalyzes ATP-to-ITP conversion in vitro and induces the massive accumulation of inosine mononucleotides during phage infection in vivo, limiting phage replication. Our results define ATP mononucleotide deamination as a determinant of RADAR immunity and reveal supramolecular assembly of a nucleotide-modifying machine as a mechanism of anti-phage defense.
Journal of Clinical Oncology
Adjuvant Endocrine Therapy in Premenopausal Breast Cancer: 12-Year Results From SOFT
Burstein HJ, Gelber RD, Regan MM
Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.The Suppression of Ovarian Function Trial (SOFT; ClinicalTrials.gov identifier: NCT00066690) randomly assigned premenopausal women with hormone receptor-positive breast cancer to 5 years of adjuvant tamoxifen, tamoxifen plus ovarian function suppression (OFS), or exemestane plus OFS. The primary analysis compared disease-free survival (DFS) between tamoxifen plus OFS versus tamoxifen alone; exemestane plus OFS versus tamoxifen was a secondary objective. After 8 years, SOFT reported a significant reduction in recurrence and improved overall survival (OS) with adjuvant tamoxifen plus OFS versus tamoxifen alone. Here, we report outcomes after median follow-up of 12 years. DFS remained significantly improved with tamoxifen plus OFS versus tamoxifen (hazard ratio, 0.82; 95% CI, 0.69 to 0.98) with a 12-year DFS of 71.9% with tamoxifen, 76.1% with tamoxifen plus OFS, and 79.0% with exemestane plus OFS. OS was improved with tamoxifen plus OFS versus tamoxifen (hazard ratio, 0.78; 95% CI, 0.60 to 1.01) and was 86.8% with tamoxifen, 89.0% with tamoxifen plus OFS, and 89.4% with exemestane plus OFS at 12 years. Among those who received prior chemotherapy for human epidermal growth factor receptor-2-negative tumors, OS was 78.8% with tamoxifen, 81.1% with tamoxifen plus OFS, and 84.4% with exemestane plus OFS. In conclusion, after 12 years, there remains a benefit from including OFS in adjuvant endocrine therapy, with an absolute improvement in OS more apparent with higher baseline risk of recurrence
Journal of Clinical Oncology
D'Amico AV
PURPOSE: Both the performance characteristics of prostate-specific membrane antigen positron emission tomography and insurance approval improves with increasing prostate-specific antigen (PSA) level causing some physicians to delay post-radical prostatectomy salvage radiation therapy (sRT) after PSA failure. Yet, it is unknown for men with at most one high-risk factor (ie, pT3/4 or prostatectomy [p] Gleason score 8-10) whether a PSA level exists above which initiating sRT is associated with increased all-cause mortality (ACM)-risk and was investigated.
METHODS: Using a multinational database of 25,551 patients with pT2-4N0 or NXM0 prostate cancer, multivariable Cox regression analysis evaluated whether an association with a significant increase in ACM-risk existed when sRT was delivered above a prespecified PSA level beginning at 0.10 ng/mL and in 0.05 increments up to 0.50 ng/mL versus at or below that level. The model was adjusted for age at and year of radical prostatectomy, established prostate cancer prognostic factors, institution, and the time-dependent use of androgen deprivation therapy.
RESULTS: After a median follow-up of 6.00 years, patients who received sRT at a PSA level >0.25 ng/mL had a significantly higher ACM-risk (AHR, 1.49; 95% CI, 1.11 to 2.00; P = .008) compared with men who received sRT when the PSA was ?0.25 mg/mL. This elevated ACM-risk remained significant for all PSA cutpoints up to 0.50 ng/mL but was not significant at PSA cutpoint values below 0.25 ng/mL.
CONCLUSION: Among patients with at most one high-risk factor, initiating sRT above a PSA level of 0.25 ng/mL was associated with increased ACM-risk.
Journal of Clinical Oncology
Reply to G.-F. Li et al, K. Altundag, and N. SG et al.
Bardia A, Tolaney SM
We thank Li et al for their interest in our manuscript and their detailed comments regarding informative censoring. Although imbalances in follow-up time between the sacituzumab govitecan (SG) and chemotherapy groups exist in progression-free survival (PFS) per blinded independent central review (BICR) as shown in the author's comments by using the reverse Kaplan-Meier (KM) and the restricted mean survival time difference methods, these methods are commonly used for estimating the follow-up time and are not generally used to determine whether censoring in a study is informative or noninformative. It is important to note that censoring imbalance between treatment groups does not necessarily indicate that censoring is related to the risk of an event (informative censoring) in the same way that balanced censoring is not a validation of noninformative censoring.
JAMA Oncology
Riaz IB, Ravi P, Sweeney C, Van Allen EM, Bryce AH
IMPORTANCE: The effectiveness of triplet therapy compared with androgen pathway inhibitor (API) doublets in a heterogeneous patient population with metastatic castration-sensitive prostate cancer (mCSPC) is unknown.
OBJECTIVE: To assess the comparative effectiveness of contemporary systemic treatment options for patients with mCSPC across clinically relevant subgroups.
DATA SOURCES: For this systematic review and meta-analysis, Ovid MEDLINE and Embase were searched from each database's inception (MEDLINE, 1946; Embase, 1974) through June 16, 2021. Subsequently, a "living" auto search was created with weekly updates to identify new evidence as it became available.
STUDY SELECTION: Phase 3 randomized clinical trials (RCTs) assessing first-line treatment options for mCSPC.
DATA EXTRACTION AND SYNTHESIS: Two independent reviewers extracted data from eligible RCTs. The comparative effectiveness of different treatment options was assessed with a fixed-effect network meta-analysis. Data were analyzed on July 10, 2022.
MAIN OUTCOMES AND MEASURES: Outcomes of interest included overall survival (OS), progression-free survival (PFS), grade 3 or higher adverse events, and health-related quality of life.
RESULTS: This report included 10 RCTs with 11?043 patients and 9 unique treatment groups. Median ages of the included population ranged from 63 to 70 years. Current evidence for the overall population suggests that the darolutamide (DARO) triplet (DARO?+?docetaxel [D]?+?androgen deprivation therapy [ADT]; hazard ratio [HR], 0.68; 95% CI, 0.57-0.81), as well as the abiraterone (AAP) triplet (AAP?+?D?+?ADT; HR, 0.75; 95% CI, 0.59-0.95), are associated with improved OS compared with D doublet (D?+?ADT) but not compared with API doublets. Among patients with high-volume disease, AAP?+?D?+?ADT may improve OS compared with D?+?ADT (HR, 0.72; 95% CI, 0.55-0.95) but not compared with AAP?+?ADT, enzalutamide (E)?+?ADT, and apalutamide (APA)?+?ADT. For patients with low-volume disease, AAP?+?D?+?ADT may not improve OS compared with APA?+?ADT, AAP?+?ADT, E?+?ADT, and D?+?ADT.
CONCLUSIONS AND RELEVANCE: The potential benefit observed with triplet therapy must be interpreted with careful accounting for the volume of disease and the choice of doublet comparisons used in the clinical trials. These findings suggest an equipoise to how triplet regimens compare with API doublet combinations and provide direction for future clinical trials.
Lancet Oncology
Tolaney SM, Tarantino P, Graham N, Tayob N, Moy B, DeMeo M, DiLullo M, Zanudo JGT, Weiss J, Wagle N, Partridge AH, Waks AG, Krop IE, Burstein HJ, Winer EP
BACKGROUND: We aimed to report on long-term outcomes of patients with small, node-negative, HER2-positive breast cancer treated with adjuvant paclitaxel and trastuzumab and to establish potential biomarkers to predict prognosis.
METHODS: In this open-label, single-arm, phase 2 study, patients aged 18 years or older, with small (?3 cm), node-negative, HER2-positive breast cancer, and an Eastern Cooperative Oncology Group performance status of 0-1, were recruited from 16 institutions in 13 cities in the USA. Eligible patients were given intravenous paclitaxel (80 mg/m2) with intravenous trastuzumab (loading dose of 4 mg/kg, subsequent doses 2 mg/kg) weekly for 12 weeks, followed by trastuzumab (weekly at 2 mg/kg or once every 3 weeks at 6 mg/kg) for 40 weeks to complete a full year of trastuzumab. The primary endpoint was 3-year invasive disease-free survival. Here, we report 10-year survival outcomes, assessed in all participants who received protocol-defined treatment, with exploratory analyses using the HER2DX genomic tool. This study is registered on ClinicalTrials.gov, NCT00542451, and is closed to accrual.
FINDINGS: Between Oct 29, 2007, and Sept 3, 2010, 410 patients were enrolled and 406 were given adjuvant paclitaxel and trastuzumab and included in the analysis. Mean age at enrolment was 55 years (SD 10·5), 405 (99·8%) of 406 patients were female and one (0·2%) was male, 350 (86·2%) were White, 28 (6·9%) were Black or African American, and 272 (67·0%) had hormone receptor-positive disease. After a median follow-up of 10·8 years (IQR 7·1-11·4), among 406 patients included in the analysis population, we observed 31 invasive disease-free survival events, of which six (19·4%) were locoregional ipsilateral recurrences, nine (29·0%) were new contralateral breast cancers, six (19·4%) were distant recurrences, and ten (32·3%) were all-cause deaths. 10-year invasive disease-free survival was 91·3% (95% CI 88·3-94·4), 10-year recurrence-free interval was 96·3% (95% CI 94·3-98·3), 10-year overall survival was 94·3% (95% CI 91·8-96·8), and 10-year breast cancer-specific survival was 98·8% (95% CI 97·6-100). HER2DX risk score as a continuous variable was significantly associated with invasive disease-free survival (hazard ratio [HR] per 10-unit increment 1·24 [95% CI 1·00-1·52]; p=0·047) and recurrence-free interval (1·45 [1·09-1·93]; p=0·011).
INTERPRETATION: Adjuvant paclitaxel and trastuzumab is a reasonable treatment standard for patients with small, node-negative, HER2-positive breast cancer. The HER2DX genomic tool might help to refine the prognosis for this population.
FUNDING: Genentech.
Lancet Oncology
Choueiri TK, McGregor B
BACKGROUND: In the primary analysis of the CLEAR study, lenvatinib plus pembrolizumab significantly improved progression-free survival and overall survival versus sunitinib in patients with advanced renal cell carcinoma (data cutoff Aug 28, 2020). We aimed to assess overall survival based on 7 months of additional follow-up.
METHODS: This is a protocol-prespecified updated overall survival analysis (data cutoff March 31, 2021) of the open-label, phase 3, randomised CLEAR trial. Patients with clear-cell advanced renal cell carcinoma who had not received any systemic anticancer therapy for renal cell carcinoma, including anti-vascular endothelial growth factor therapy, or any systemic investigational anticancer drug, were eligible for inclusion from 200 sites (hospitals and cancer centres) across 20 countries. Patients were randomly assigned (1:1:1) to receive lenvatinib (20 mg per day orally in 21-day cycles) plus pembrolizumab (200 mg intravenously every 21 days; lenvatinib plus pembrolizumab group), lenvatinib (18 mg per day orally) plus everolimus (5 mg per day orally; lenvatinib plus everolimus group [not reported in this updated analysis]) in 21-day cycles, or sunitinib (50 mg per day orally, 4 weeks on and 2 weeks off; sunitinib group). Eligible patients were at least 18 years old with a Karnofsky performance status of 70 or higher. A computer-generated randomisation scheme was used, and stratification factors were geographical region and Memorial Sloan Kettering Cancer Center prognostic groups. The primary endpoint was progression-free survival assessed by independent imaging review according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1). In this Article, extended follow-up analyses for progression-free survival and protocol-specified updated overall survival data are reported for the intention-to-treat population. No safety analyses were done at this follow-up. This study is closed to new participants and is registered with ClinicalTrials.gov, NCT02811861.
FINDINGS: Between Oct 13, 2016, and July 24, 2019, 1417 patients were screened for inclusion in the CLEAR trial, of whom 1069 (75%; 273 [26%] female, 796 [74%] male; median age 62 years [IQR 55-69]) were randomly assigned: 355 (33%) patients (255 [72%] male and 100 [28%] female) to the lenvatinib plus pembrolizumab group, 357 (33%) patients (275 [77%] male and 82 [23%] female) to the sunitinib group, and 357 (33%) patients to the lenvatinib plus everolimus group (not reported in this updated analysis). Median follow-up for progression-free survival was 27·8 months (IQR 20·3-33·8) in the lenvatinib plus pembrolizumab group and 19·4 months (5·5-32·5) in the sunitinib group. Median progression-free survival was 23·3 months (95% CI 20·8-27·7) in the lenvatinib plus pembrolizumab group and 9·2 months (6·0-11·0) in the sunitinib group (stratified hazard ratio [HR] 0·42 [95% CI 0·34-0·52]). Median overall survival follow-up was 33·7 months (IQR 27·4-36·9) in the lenvatinib plus pembrolizumab group and 33·4 months (26·7-36·8) in the sunitinib group. Overall survival was improved with lenvatinib plus pembrolizumab (median not reached [95% CI 41·5-not estimable]) versus sunitinib (median not reached [38·4-not estimable]; HR 0·72 [95% CI 0·55-0·93]).
INTERPRETATION: Efficacy benefits of lenvatinib plus pembrolizumab over sunitinib were durable and clinically meaningful with extended follow-up. These results support the use of lenvatinib plus pembrolizumab as a first-line therapy for patients with advanced renal cell carcinoma.
FUNDING: Eisai and Merck Sharp & Dohme.
Nature
Lactate Regulates Cell Cycle by Remodeling the Anaphase Promoting Complex
Liu W, Wang Y, Bozi LHM, Fischer P, Jedrychowski MP, Xiao H, Wu T, Darabedian N, He X, Mills EL, Burger N, Shin S, Reddy A, Sprenger HG, Tran N, Winther S, Seo HS, Song K, Xu AZ, Sebastian L, Zhao J, Dhe-Paganon S, Che J, Gygi SP, Arthanari H, Chouchani ET
Lactate is abundant in rapidly dividing cells due to the requirement for elevated glucose catabolism to support proliferation1-6. However, it is not known whether accumulated lactate affects the proliferative state. Here, we deploy a systematic approach to determine lactate-dependent regulation of proteins across the human proteome. From these data, we elucidate a mechanism of cell cycle regulation whereby accumulated lactate remodels the anaphase promoting complex (APC/C). Remodeling of APC/C in this way is caused by direct inhibition of the SUMO protease SENP1 by lactate. We discover that accumulated lactate binds and inhibits SENP1 by forming a complex with zinc in the SENP1 active site. SENP1 inhibition by lactate stabilizes SUMOylation of two residues on APC4, which drives UBE2C binding to APC/C. This direct regulation of APC/C by lactate stimulates timed degradation of cell cycle proteins, and efficient mitotic exit in proliferative human cells. The above mechanism is initiated upon mitotic entry when lactate abundance reaches its apex. In this way, accumulation of lactate communicates the consequences of a nutrient replete growth phase to stimulate timed opening of APC/C, cell division, and proliferation. Conversely, persistent accumulation of lactate drives aberrant APC/C remodeling and can overcome anti-mitotic pharmacology via mitotic slippage. Taken together, we define a biochemical mechanism through which lactate directly regulates protein function to control cell cycle and proliferation.
Nature
MEN1 Mutations Mediate Clinical Resistance to Menin Inhibition
Perner F, Wenge DV, Kim J, Apazidis A, Rahnamoun H, Anand D, Marinaccio C, Hatton C, Wen Y, Stone RM, Ener E, Cutler JA, Doench JG, Nowak RP, Fischer ES, Armstrong SA
Chromatin-binding proteins are critical regulators of cell state in haematopoiesis1,2. Acute leukaemias driven by rearrangement of the mixed lineage leukaemia 1 gene (KMT2Ar) or mutation of the nucleophosmin gene (NPM1) require the chromatin adapter protein menin, encoded by the MEN1 gene, to sustain aberrant leukaemogenic gene expression programs3-5. In a phase 1 first-in-human clinical trial, the menin inhibitor revumenib, which is designed to disrupt the menin-MLL1 interaction, induced clinical responses in patients with leukaemia with KMT2Ar or mutated NPM1 (ref. 6). Here we identified somatic mutations in MEN1 at the revumenib-menin interface in patients with acquired resistance to menin inhibition. Consistent with the genetic data in patients, inhibitor-menin interface mutations represent a conserved mechanism of therapeutic resistance in xenograft models and in an unbiased base-editor screen. These mutants attenuate drug-target binding by generating structural perturbations that impact small-molecule binding but not the interaction with the natural ligand MLL1, and prevent inhibitor-induced eviction of menin and MLL1 from chromatin. To our knowledge, this study is the first to demonstrate that a chromatin-targeting therapeutic drug exerts sufficient selection pressure in patients to drive the evolution of escape mutants that lead to sustained chromatin occupancy, suggesting a common mechanism of therapeutic resistance.
Nature Chemical Biology
Velcrin-Induced Selective Cleavage of tRNA(Leu)(TAA) by SLFN12 Causes Cancer Cell Death
Lee S, Hoyt S, Wu X, Garvie C, McGaunn J, Shekhar M, Tötzl M, Rees MG, Cherniack AD,
Meyerson M, Greulich H
Velcrin compounds kill cancer cells expressing high levels of phosphodiesterase 3A (PDE3A) and Schlafen family member 12 (SLFN12) by inducing complex formation between these two proteins, but the mechanism of cancer cell killing by the PDE3A-SLFN12 complex is not fully understood. Here, we report that the physiological substrate of SLFN12 RNase is tRNALeu(TAA). SLFN12 selectively digests tRNALeu(TAA), and velcrin treatment promotes the cleavage of tRNALeu(TAA) by inducing PDE3A-SLFN12 complex formation in vitro. We found that distinct sequences in the variable loop and acceptor stem of tRNALeu(TAA) are required for substrate digestion. Velcrin treatment of sensitive cells results in downregulation of tRNALeu(TAA), ribosome pausing at Leu-TTA codons and global inhibition of protein synthesis. Velcrin-induced cleavage of tRNALeu(TAA) by SLFN12 and the concomitant global inhibition of protein synthesis thus define a new mechanism of apoptosis initiation.
Nature Communications
Patterson-Fortin J, Jadhav H, Pantelidou C, Phan T, Grochala C, Mehta AK, Guerriero JL, Wulf GM, Wolpin BM, Aguirre AJ, Cleary JM, D'Andrea AD, Shapiro GI
Recently developed inhibitors of polymerase theta (POL?) have demonstrated synthetic lethality in BRCA-deficient tumor models. To examine the contribution of the immune microenvironment to antitumor efficacy, we characterized the effects of POL? inhibition in immunocompetent models of BRCA1-deficient triple-negative breast cancer (TNBC) or BRCA2-deficient pancreatic ductal adenocarcinoma (PDAC). We demonstrate that genetic POLQ depletion or pharmacological POL? inhibition induces both innate and adaptive immune responses in these models. POL? inhibition resulted in increased micronuclei, cGAS/STING pathway activation, type I interferon gene expression, CD8+ T cell infiltration and activation, local paracrine activation of dendritic cells and upregulation of PD-L1 expression. Depletion of CD8+ T cells compromised the efficacy of POL? inhibition, whereas antitumor effects were augmented in combination with anti-PD-1 immunotherapy. Collectively, our findings demonstrate that POL? inhibition induces immune responses in a cGAS/STING-dependent manner and provide a rationale for combining POL? inhibition with immune checkpoint blockade for the treatment of HR-deficient cancers.
Abdominal Radiology
Glazer DI, Mayo-Smith WW, Brook OR, Shinagare AB, Blake MA
AJR American Journal of Roentgenology
Beyond the AJR: CT Radiomic Features of the Pancreas Predict Development of Pancreatic Cancer
Rosenthal MH, Schawkat K
American Journal of Hematology
Acute Myeloid Leukemia: 2023 Update on Diagnosis, Risk-Stratification, and Management
Shimony S, Stahl M, Stone RM
Angewandte Chemie International Edition
Targeting the Dark Lipid Kinase PIP4K2C with a Potent and Selective Binder and Degrader
Teng M, Jiang J, Donovan KA, Mageed N, Yue H, Nowak RP, Wang J, Manz TD, Fischer ES,
Cantley LC
Bioinformatics
AGC: Compact Representation of Assembled Genomes with Fast Queries and Updates
Li H
Blood Cancer Discovery
Ten Hacken E, Sewastianik T, Yin S, Hoffmann GB, Clement K, Penter L, Redd RA, Ruthen N, Fell G, Parry EM, Lucas F, Baranowski K, Southard J, Joyal H, Billington L, Regis FFD, Witten E, Uduman M, Knisbacher BA, Li S, Lyu H, Davids MS, Getz G, Livak KJ, Neuberg DS, Carrasco RD, Wu CJ
British Journal of Sports Medicine
Ma C, Meyerhardt JA
Breast Cancer Research and Treatment
Bychkovsky BL, Garber JE, Scheib R, Rana HQ
CA Cancer Journal for Clinicians
Nishino M, Sholl LM, Silvestri GA, Johnson BE
Cancer Epidemiology, Biomarkers, and Prevention
Elucidating Analytic Bias Due to Informative Cohort Entry in Cancer Clinico-Genomic Datasets
Kehl KL, Uno H, Gusev A, Groha S
Cancer Immunology, Immunotherapy
Phase II Trial of CV301 Vaccine Combined with Atezolizumab in Advanced Urothelial Carcinoma
Morimoto Y, Yamashita N, Fushimi A, Haratake N, Daimon T, Bhattacharya A, Ahmad R, Kufe DW
Cancer Nursing
Knoerl R, Wallar J, Fox E, Hong F, Salehi E, McCleary N, Ligibel JA, Reyes K
Cancer Nursing
A Systematic Review and Meta-analytic Evaluation of Moral Distress in Oncology Nursing
Eche IJ, Phillips CS, Alcindor N, Mazzola E
Cancer Nursing
Translation of Evidence-Based Interventions into Oncology Care Settings: An Integrative Review
Cooley ME, Hammer MJ
Cancer Research
Mitochondrial DNA Mutations as Natural Barcodes for Lineage Tracing of Murine Tumor Models
Penter L, Ten Hacken E, Southard J, Li S, Neuberg DS, Livak KJ, Wu CJ
Cell Metabolism
Mittenbühler MJ, Jedrychowski MP, Van Vranken JG, Sprenger HG, Wilensky S, Dumesic PA, Sun Y, Tartaglia A, Bogoslavski D, A M, Xiao H, Blackmore KA, Reddy A, Gygi SP, Chouchani ET, Spiegelman BM
Cell Reports
IFN? is a Central Node of Cancer Immune Equilibrium
Walsh MJ, Stump CT, Kureshi R, Lenehan P, Ali LR, Dougan M, Knipe DM, Dougan SK
Clinical Cancer Research
Chen EC, Toši? I, Fell GG, Pozdnyakova O, DeAngelo DJ, Galinsky I, Luskin MR, Wadleigh M,
Winer ES, Leonard R, Neuberg D, Look AT, Stone RM, Garcia JS
Clinical Lymphoma, Myeloma and Leukemia
SOHO State of the Art Updates and Next Questions: Treatment of Lower Risk Myelodysplastic Syndromes
Volpe VO
Clinical and Translational Gastroenterology
Lee AA, Wang QL, Kim J, Babic A, Zhang X, Perez K, Ng K, Nowak J, Rifazzzzzzzzgi N, Sesso HD, Buring JE, Manson JE, Giovannucci EL, Stampfer MJ, Kraft P, Yuan C, Wolpin BM
European Journal of Cancer
Prospectively Shared Control Data Across Concurrent Randomised Clinical Trials
Kotecha G, Trippa L
Haematologica
The Development of Graft-Versus-Host Disease Prophylaxis
Cutler C
International Journal of Radiation Oncology, Biology, Physics
Geographic Accessibility of Radiation Therapy Facilities in Sub-Saharan Africa
Iyer HS, Triedman SA, Fadelu T
Journal of Clinical Investigation
YAP1 and WWTR1 Expression Inversely Correlates with Neuroendocrine Markers in Merkel cell Carcinoma
Frost TC, Gartin AK, Liu M, Cheng J, Dharaneeswaran H, Keskin DB, Wu CJ, Giobbie-Hurder A, Thakuria M, DeCaprio JA
Journal of Clinical Medicine
Sattler M
Journal of Clinical Sleep Medicine
Zhou ES, Revette A, Heckler GK, Worhach J, Maski K, Owens JA
Journal of Gastroenterology
Ugai T, Akimoto N, Haruki K, Chan AT, Nishihara R, Meyerhardt JA, Giannakis M, Song M, Nowak JA, Ogino S
Journal of Neuro-Oncology
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