Dana-Farber Research News 08.15.2026
Welcome to Dana-Farber's Research News
August 15, 2026
This twice-monthly newsletter highlights recently published research where Dana-Farber faculty are listed as first or senior authors. The information is pulled from PubMed and this issue notes papers published from July 16 - 31.
If you are a Dana-Farber faculty member and you think your paper is missing from Research News, please let us know by emailing dfciresearchnews@dfci.harvard.edu.
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Blood Maisano D, Kulp SB, Cumerlato M, Li C, Barello F, Garbicz F, Ladisa F, Chakraborty C, Vreux L, Aktas Samur A, Samur MK, Carrasco RD, Fulciniti M, Anderson KC, Munshi NC The c-MYC (MYC) oncogene is a critical driver of multiple myeloma (MM), however, direct targeting of the MYC protein has proven challenging due to its intrinsic structural disorder. In this study, we evaluated the biological activity and molecular mechanism of a ribonuclease-targeting chimera (RiboTAC) designed to promote the degradation of MYC mRNA (MYC-RiboTAC) across a panel of primary patient MM samples and MM cell lines. This heterobifunctional molecule consists of a small molecule targeting the MYC internal ribosomal entry site (IRES) conjugated to a small-molecule recruiter of endogenous RNaseL. The MYC-RiboTAC reduces MYC mRNA and protein levels in an RNase L-dependent manner, selectively inhibits MYC-driven transcriptional programs, and exhibits potent anti-MM activity. It effectively suppresses cell growth in MM cells co-expressing MYC and RNase L, even in the presence of the protective bone marrow. Furthermore, it synergizes with clinically active agents such as carfilzomib, lenalidomide, and pomalidomide. Importantly, MYC-RiboTAC displays favorable safety and pharmacokinetic profiles in mice and significantly suppresses tumor growth in NOD SCID mice bearing MM xenografts, as shown in two different models. These findings highlight the potential of RNA degraders to target mRNAs encoding "undruggable" proteins such as MYC, offering a promising avenue for precision cancer therapy. |
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Blood Weeks LD, Neuberg DS, Wang Y, Lindsley RC Sickle cell disease (SCD) is an inherited hemoglobinopathy characterized by chronic hemolytic anemia, painful vaso-occlusive episodes, and end-organ damage. Cellular therapies, including allogeneic hematopoietic cell transplant (allo-HCT) and gene therapy, are potentially curative treatments for SCD. Cases of myelodysplastic syndrome and acute myeloid leukemia (MDS/AML) occurring after cellular therapy for SCD and reports of an increased relative risk of AML in populations with SCD have raised questions about the association between SCD and clonal hematopoiesis (CH), a recognized precursor state for MDS/AML. We used error-corrected DNA sequencing to detect CH variants at a variant allele fraction > 0.0005 in blood samples from 98 individuals with SCD and 72 non-SCD donor controls who underwent HCT at the NIH between July 2004 and June 2023. Baseline CH prevalence was similar in recipients and donors; however, SCD recipients had 3.8-fold higher odds of DNA Damage Response (DDR)-mutant CH, involving TP53, PPM1D, ATM, and CHEK2, compared with non-SCD donors. Following HCT, the proportion of SCD recipients with CH increased, driven primarily by mutations in DNMT3A/TET2 and TP53. Post-HCT CH arose from newly emergent variants undetectable at baseline in both recipient and paired donor samples, engrafted donor-derived CH, and persistent recipient CH. All cases of donor-derived CH involved DNMT3A/TET2 mutations, while persistent-recipient CH involved DDR mutations. Hematologic malignancies were rare but included 3 cases of fatal TP53-mutant MDS/AML. Larger cohort studies are needed to identify risk factors for developing DDR-CH and MDS/AML in SCD and to optimize cellular therapy safety in this population. |
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Blood Crombie JL, Frigault MJ This study assessed real-world effectiveness and safety of lisocabtagene maraleucel (liso-cel) in patients with relapsed/refractory (R/R) large B-cell lymphoma (LBCL), including those with high-risk disease, secondary central nervous system (sCNS) involvement, comorbidities, and poor fitness, using data in the Center for International Blood and Marrow Transplant Research Registry from 5 February 2021 to 4 February 2025. Eligible patients (N = 1116) received liso-cel and had ?1 effectiveness and safety assessment after infusion, including 195 in the second-line setting, 71 with sCNS, and 257 with transformed LBCL. Median age was 71.1 years (range, 21.5-91.2), with 72.3% aged ?65 years. Within the overall population, 6.6% had an Eastern Cooperative Oncology Group performance status of ?2, 53.4% had ?1 comorbidity, and the median number of previous lines of therapy was 3 (range, 1-16). Median study follow-up was 12.6 months (95% confidence interval [CI], 12.5-12.8). Among effectiveness-evaluable patients (n = 1109), objective response rate was 81.2% and complete response rate was 71.3%. Duration of response, progression-free survival, and overall survival rates at 12 months were 60.2% (95% CI, 56.4-63.9), 51.2% (95% CI, 48.0-54.4), and 67.6% (95% CI, 64.5-70.6), respectively. Cytokine release syndrome was reported in 51.0% of patients, with grade ?3 events in 2.5%. Immune effector cell-associated neurotoxicity syndrome was reported in 26.6% of patients, with grade ?3 events in 9.2%. The 12-month nonrelapse mortality rate was 6.1% (95% CI, 4.6-7.8). These real-world data reinforce the effectiveness and safety of liso-cel in this broad population of patients with R/R LBCL, including younger patients and those with high-risk disease features. |
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Journal of Clinical Oncology Pollard JA, Place A PURPOSE: The Children's Oncology Group phase III clinical trial AAML1831 (ClinicalTrials.gov identifier: NCT04293562) evaluated liposomal daunorubicin and cytarabine (CPX-351) versus standard daunorubicin/cytarabine (DA) induction therapy in children and young adults with newly diagnosed AML. We hypothesized that CPX-351 given during induction 1 and 2 would improve outcomes compared with DA. PATIENTS AND METHODS: Patients (21 years and younger) were randomly assigned to two cycles of DA induction (arm A = DA) or CPX-351 (arm B = CPX-351). All patients also received gemtuzumab ozogamicin in induction 1. Postinduction chemotherapy was according to risk assignment made at the end of induction 1 (EOI1). Those with high-risk (HR) AML received consolidation with allogeneic hematopoietic stem-cell transplantation (HSCT), whereas low-risk (LR) patients received chemotherapy alone. Protocol-specified interim analysis monitored efficacy and futility of CPX-351 induction with respect to the primary end point, event-free survival (EFS) from study entry. Disease-free survival (DFS) was calculated to determine the impact of EOI1 risk assignment. RESULTS: Seven hundred twenty-one eligible patients with FLT3 wild-type AML were randomly assigned to DA (n = 358) or CPX-351 (n = 363). Interim analysis determined that the futility monitoring rule was crossed because of inferior EFS in the CPX-351 arm and the random assignment was stopped. The two-year EFS from study entry was 62.2% for DA versus 51.2% for CPX-351 (P = .011). DFS for patients with HR AML was comparable for both arms. However, DFS was significantly lower and cumulative incidence of relapse (CIR) was higher for LR patients assigned to CPX-351 versus DA (2-year DFS from EOI1: DA: 73.8% v CPX-351 57.5% [P = .001]; 2-year CIR Arm DA: 23.6% v CPX-351: 39.9% [P = .001]). CONCLUSION: CPX-351 was inferior to DA induction in the AAML1831 trial with differential EFS largely driven by events in LR patients. |
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Journal of Clinical Oncology Beltran H, Berg S, Choudhury AD, Jacene HA, McGregor B, Choueiri TK PURPOSE: Bone metastases (BM) occur in approximately 30% of patients with metastatic renal cell carcinoma (mRCC) and are associated with poor survival and symptomatic skeletal events (SSEs). Radium-223, an alpha-emitting bone-seeking radioisotope, and cabozantinib, a tyrosine kinase inhibitor, have demonstrated activity in BM. RADICAL (Alliance A031801; ClinicalTrials.gov identifier: NCT04071223) evaluated cabozantinib ± radium-223 in mRCC with BM. METHODS: This phase II trial enrolled patients with mRCC of any histology with ?1 BM. Patients were randomly assigned 1:1 to cabozantinib ± radium-223, stratified by osteoclast-targeted therapy (OTT), prior therapy, opioid use, and International mRCC Database Consortium (IMDC) risk. The primary end point was SSE-free survival (SSE-FS). Secondary end points included safety, objective response rate (ORR), progression-free survival, and overall survival (OS). A target of 124 evaluable patients was planned, with a prespecified interim futility analysis at 50% of expected SSE-FS events; the trial would stop if the stratified hazard ratio (sHR) > 1.0. RESULTS: The prespecified interim futility analysis was conducted after 90 patients were enrolled and crossed the futility boundary, leading to closure at 98 patients. The final analysis included all 98 patients. Median age was 63 years, 82.7% had clear cell histology, and 79.6% were using an OTT. IMDC risk was favorable (18.4%), intermediate (67.3%), and poor (14.3%). Median follow-up was 13.1 months. Median SSE-FS for cabozantinib with radium-223 versus cabozantinib was 16.7 versus 17.6 months (sHR, 1.46 [90% CI, 0.86 to 2.51]). Median OS was 28.3 versus 19.7 months (sHR, 1.40 [95% CI, 0.70 to 2.79]). ORR was 19.4% versus 25.0% (P = .78). Grade ?3 adverse events were similar across arms (69.6% v 75.5%). CONCLUSION: Radium-223 did not improve SSE-FS when added to cabozantinib. The combination demonstrated a manageable safety profile. |
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Journal of Clinical Oncology Rudra Gupta T, Redd R, Lee EQ, Arrillaga-Romany I, Tan Y, Chukwueke UN, Beroukhim R, Nayak L, Batchelor TT, Bi WL, Arnaout O, Peruzzi PP, Haas-Kogan D, Tanguturi S, Aizer A, Doherty L, Santagata S, Meredith DM, Chiocca EA, Reardon DA, Ligon KL, Trippa L, Rahman R PURPOSE: Integrating external control data into clinical trial designs and analyses has the potential to accelerate drug development processes. We reanalyzed the three experimental arms of the Individual Screening Trial of Innovative Glioblastoma Therapy (INSIGhT), a randomized phase II platform trial in newly diagnosed O6-methylguanine-DNA methyltransferase-unmethylated glioblastoma (ClinicalTrials.gov identifier: NCT02977780). To evaluate the validity of using external data sets, we compared treatment effect estimates based on internal INSIGhT control data and matched external control data. METHODS: The three experimental arms of INSIGhT (abemaciclib [n = 72], neratinib [n = 80], and CC-115 [n = 12]) did not improve survival compared with internal controls (standard chemoradiation [n = 70]). We derived external control patient-level data from multiple real-world and clinical trial data sets. We applied propensity score matching and Cox proportional hazards models to estimate treatment effects with external controls. Additionally, using this glioblastoma (GBM) data collection, we specified simulation scenarios to evaluate trial designs that integrate external controls. RESULTS: After matching to external controls, no survival benefit was observed for patients receiving abemaciclib (hazard ratio [HR], 1.00 [95% CI, 0.75 to 1.34]), neratinib (HR, 0.93 [95% CI, 0.70 to 1.24]), or CC-115 (HR, 0.88 [95% CI, 0.41 to 1.88]). Simulations, together with the INSIGhT data and a collection of GBM data sets, allowed us to examine efficiencies and risks of clinical trial designs that leverage external control data. CONCLUSION: The use of carefully matched external controls, to replace or augment the internal controls of INSIGhT, produced treatment effect estimates that were similar to previously published analyses. Single-arm trial designs and hybrid randomized designs incorporating propensity score-matched external control data evaluated treatment effects in the early-phase testing of experimental therapies in newly diagnosed GBM. The validity of this approach and risks of bias depended on the availability of comprehensive and accurate data on all potential confounders, in the absence of unmeasured confounding. |
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Lancet Hartley-Brown MA, Richardson PG BACKGROUND: A growing number of patients with multiple myeloma are anti-CD38 antibody-exposed and lenalidomide-exposed at first relapse, subsequently limiting their treatment options. Mezigdomide, a potent cereblon E3 ligase modulator, induces maximal, rapid Ikaros and Aiolos degradation, resulting in enhanced myeloma cell cytotoxicity and immune stimulation versus immunomodulatory drugs. The SUCCESSOR-2 trial evaluates the efficacy and safety of mezigdomide in combination with carfilzomib and dexamethasone versus carfilzomib plus dexamethasone. METHODS: This phase 3, open-label, randomised controlled trial was conducted at 160 hospital-based sites in 26 countries using a two-stage, inferentially seamless design. Eligible adult patients had measurable multiple myeloma, had received at least one previous regimen (including anti-CD38 antibodies and lenalidomide) on which they had achieved minimal response or better, and documented disease progression during or after their most recent treatment. Interactive response technology was used to randomly assign patients, stratified by age (?70 years or >70 years), number of previous lines of therapy (?2 or >2), and International Staging System stage (I, II, or III). Patients received oral mezigdomide (days 1-21 of each 28-day cycle) plus intravenous carfilzomib (56 mg/m2 weekly) and oral or intravenous dexamethasone (40 mg weekly) or carfilzomib (56 mg/m2 twice weekly or 70 mg/m2 weekly) and dexamethasone (20 mg twice weekly or 40 mg weekly). In stage 1, mezigdomide dosing across three levels was optimised. In stage 2, patients were randomly assigned to the selected mezigdomide dose (1·0 mg) plus carfilzomib and dexamethasone or carfilzomib-dexamethasone alone. The primary endpoint was progression-free survival (PFS) evaluated in patients who received 1·0 mg mezigdomide plus carfilzomib and dexamethasone or carfilzomib-dexamethasone alone across both study stages. No imputation was planned for missing efficacy endpoint values or missing safety evaluations. The trial is registered with ClinicalTrials.gov (NCT05552976) and EUClinicalTrials.eu (EUCT number 2022-500861-29-00). The trial is active but not recruiting. FINDINGS: Between Feb 3, 2023, and Nov 28, 2025, 762 patients were assessed for eligibility, of which 606 patients were enrolled and 479 were included in the analyses (288 patients in the mezigdomide-carfilzomib-dexamethasone group and 191 patients in the carfilzomib-dexamethasone group). 252 (53%) patients were male, 411 (86%) were anti-CD38 antibody-refractory, and 363 (76%) were lenalidomide-refractory, with a median of two previous lines of therapy (IQR 2-4). At 10·6 months median follow-up, mezigdomide-carfilzomib-dexamethasone significantly improved PFS compared with carfilzomib-dexamethasone (median 18·0 months vs 8·3 months; hazard ratio 0·48 [95% CI 0·36-0·63]; p<0·0001). Grade 3 or 4 adverse events were observed in 241 (84%) patients receiving mezigdomide-carfilzomib-dexamethasone versus 105 (56%) patients receiving carfilzomib-dexamethasone, including neutropenia (176 [61%] vs 17 [9%]) and infections (98 [34%] vs 29 [16%]). Eight (3%; 95% CI 1-5) and one (1%; 95% CI 0-3) treatment-related grade 5 adverse events were reported with mezigdomide-carfilzomib-dexamethasone and with carfilzomib-dexamethasone, respectively (rate difference 2%; 95% CI -1 to 5). Deaths occurred in 62 (22%) patients in the mezigdomide-carfilzomib-dexamethasone group and 51 (27%) patients in the carfilzomib-dexamethasone group, mainly due to disease progression. INTERPRETATION: Mezigdomide-carfilzomib-dexamethasone provided a significant PFS benefit compared with carfilzomib-dexamethasone alone, with higher rates of grade 3 or 4 adverse events, including infections, which were mostly manageable with standard clinical practice and supportive care. These findings support mezigdomide-carfilzomib-dexamethasone as a clinically meaningful treatment option as early as first relapse in predominantly triple-class-exposed, anti-CD38 antibody-refractory and lenalidomide-refractory patients, a growing population with substantial unmet need. FUNDING: Bristol Myers Squibb. |
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Molecular Cell Disruption of Microhomology-Mediated End Joining in Ewing Sarcoma Asada S, Zhu G, Abeykoon JP, Tanaka Y, Nguyen H, Hirohashi Y, Iyer DR, Ashton NW, Mukkavalli S, Velazquez M, Jiang L, Parmar K, Van Allen EM, Gillani R, Shapiro GI, D'Andrea AD Ewing sarcoma (EwS) is a group of bone and soft-tissue cancers in children and young adults. Because EwS cells have pronounced sensitivity to radiation and chemotherapy-induced DNA damage, the oncoprotein EWS-FLI1 is likely to be involved in DNA repair. Here, we demonstrate that EWS-FLI1 causes a defect in microhomology-mediated end joining (MMEJ) repair. EWSR1 is a splicing factor that promotes the faithful splicing of the POLQ pre-mRNA, required for the expression of Pol?, a critical protein in the MMEJ pathway. Expression of EWS-FLI1 or depletion of EWSR1 causes increased POLQ exon 25 skipping, decreased Pol? expression, impaired MMEJ, and enhanced cellular sensitivity to inhibitors of the Fanconi anemia (FA), homologous recombination (HR), or non-homologous end joining (NHEJ) pathways, through the mechanism of synthetic lethality. Correction of POLQ exon 25 skipping restored Pol? expression and MMEJ activity in EwS. Inhibitors of the FA, HR, or NHEJ pathways may therefore provide a targeted therapy for EwS patients. |
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Nature Tertiary Lymphoid Structures Harbour Stem-Like Tumour-Specific T Cells Afeyan AB, Nagler A, Tu CR, Roberti De Oliveira G, Simsek B, Seager MD, El Ahmar N, Sax HE, Lin E, Sud A, Borji M, Forman C, Liu S, Ott PA, Choueiri TK, Abelin JG, Li S, Livak KJ, Tyekucheva S, Keskin DB, Chen F, Simon JM, Signoretti S, Oliveira G, Braun DA, Wu CJ Tertiary lymphoid structures (TLSs) are associated with improved responses to immune checkpoint blockade across solid tumours1,2, but how they impact the phenotypic properties of tumour-specific T cells remains unclear. Here we found, across 24 treatment-naive renal cell carcinoma (RCC) tumours, that TLS-containing tumours are more heavily infiltrated by exhausted CD8+ T cells and have a reduced terminal exhaustion transcriptional program compared with TLS- tumours. Specificity screening of 554 T cell clonotypes expanded within the microenvironment of 6 RCC tumours revealed 82 TCRs that were reactive against tumour cells and/or RCC antigens. A subset of tumour-specific T cell clonotypes (12%) was enriched within TLSs, and these expressed an increased program of stem-like progenitor exhaustion, associated with favourable anti-tumour immunity. However, in 60 independent RCC tumours, macrophages within tumour margins of TLS-containing tumours had an inferred immunosuppressive phenotype and were colocalized with exhausted putative tumour-reactive T cells in a subgroup that was further analysed, therefore supporting this mode of immune evasion as a counterbalance to T cell immune pressure. Our data reveal that TLSs are reservoirs of tumour-specific T cells with stem-like progenitor features that could be leveraged by T cell immunotherapies. |
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Nature Biotechnology Nagler A, Sud A, Ghannam JY, Pomerance L, Robles-Oteiza C, Afeyan AB, Weir JA, Russell AJC, Lu WS, Van Orden M, Marrero GJ, Gong Q, Kumar V, Huang K, Tu C, Lin E, Shim B, De Oliveira GR, Sellars MC, Yoon CH, Reardon DA, Choueiri TK, Signoretti S, Ott PA, Oliveira G, Li S, Livak KJ, Hacohen N, Chen F, Wu CJ Improved methods to identify therapeutically relevant tumor neoantigens and their cognate T cells would aid the development of precision medicines for cancer. Here, we developed Slide-GoTags, a droplet-based single-nucleus spatial transcriptomics approach that characterizes neoantigen-specific immunity by integrating targeted transcript genotyping and T cell receptor (TCR) sequencing with single-nucleus RNA sequencing from the same slice of frozen tissue. Application of Slide-GoTags to mouse and human tumors revealed colocalization of clonally expanded, neoantigen-specific T cells with tumor cells expressing their cognate neoantigen. We also identified distinct spatial immune landscapes shaped by anti-PD1 or anti-CTLA4 blockade in mouse colorectal tumors. Across human tumor types, Slide-GoTags detected TCR-neoantigen interactions through spatial proximity and identified an enrichment of interferon-driven immunogenicity niches in immunologically 'hot' tumors compared to 'cold' tumors. These niches harbored three T cell clonotypes that colocalized with genotyped neoantigens, highlighting a spatially organized antitumor immune response. Collectively, Slide-GoTags establishes a framework for in situ mapping of T cell-tumor interactions directly from individual tissue. |
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Nature Communications A Computational Framework for Designing Micron-Scale Crisscross DNA Megastructures Aquilina M, Katzmeier F, Nijenhuis MAD, Wang SS, Becker C, Zhao Y, Seok SH, Finkel J, Cui H, Lee S, Shih WM Crisscross polymerization enables the assembly of hundreds of unique DNA origami 'slats' into micron-sized structures with nanoscale precision. To design these megastructures, thousands of handle sequences from a fixed library must be assigned to individual slats to encode the desired binding architecture. This complexity presents two major challenges: handles must be selected to minimize parasitic interactions that compete with desired assembly, and the fabrication of hundreds of unique slats creates a substantial logistical burden. Here, we develop a unified framework that standardizes the design and fabrication of crisscross megastructures. We use an evolutionary algorithm to optimize handle assignment and minimize parasitic binding between slats. Together with an expanded handle library, the algorithm enables the assembly of large, multi-layered megastructures that otherwise would be produced at negligible yields. We have released this framework as #-CAD, an open-source graphical application that integrates these algorithms, streamlines laboratory workflows, and makes crisscross DNA origami more broadly accessible. |
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New England Journal of Medicine Daraxonrasib or Chemotherapy in Previously Treated Metastatic Pancreatic Cancer Wolpin BM BACKGROUND: Current therapies offer limited benefit for patients with previously treated metastatic pancreatic ductal adenocarcinoma (mPDAC). Aberrant activation of the RAS pathway is the key driver of PDAC, with oncogenic RAS mutations present in more than 90% of cases. Daraxonrasib is an oral RAS(ON) multiselective, tri-complex inhibitor of the active guanosine triphosphate-bound state of mutant and wild-type RAS. METHODS: In this phase 3, international, open-label, randomized trial, we randomly assigned patients with previously treated mPDAC to receive daraxonrasib or chemotherapy of the investigator's choice. The dual primary end points were overall survival and progression-free survival in the subpopulation of patients with RAS G12 mutations (the RAS G12 population). Key secondary end points included overall survival and progression-free survival in the overall population (which included patients with RAS G12, G13, or Q61 mutations or with no RAS mutation identified) and objective response and patient-reported quality of life in the RAS G12 and overall populations. Safety was also assessed. RESULTS: A total of 500 patients, including 91.8% with RAS G12 mutations, were randomly assigned to receive daraxonrasib (248 patients) or chemotherapy (252 patients). The median overall survival in the RAS G12 population was 13.2 months with daraxonrasib and 6.6 months with chemotherapy, and the median overall survival in the overall population was 13.2 months and 6.7 months, respectively; the hazard ratio was 0.40 in both populations (P<0.001). The median progression-free survival in the RAS G12 population was 7.3 months with daraxonrasib and 3.5 months with chemotherapy, and that in the overall population was 7.2 months and 3.6 months, respectively; the hazard ratios were 0.45 and 0.49, respectively (P<0.001 for both comparisons). Adverse events that occurred after the start of treatment were reported in all the patients in the daraxonrasib group and in 97.7% of those in the chemotherapy group; the incidence of adverse events of grade 3 or higher was 61.8% and 69.6%, respectively. Treatment-related adverse events that led to treatment discontinuation occurred in 1.2% of the patients in the daraxonrasib group and in 11.2% of those in the chemotherapy group. CONCLUSIONS: Among patients with previously treated mPDAC, treatment with daraxonrasib led to significantly longer overall survival and progression-free survival than chemotherapy. (Funded by Revolution Medicines; RASolute 302 ClinicalTrials.gov number, NCT06625320.). |
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Proceedings of the National Academy of the Sciences of the U.S.A. Oncogenic G? Signaling Requires AP-3-Dependent Recruitment to the Endolysosomal Compartment Shettigar M, Moulière S, Isenegger L, DeVine AL, Gstalder C, Koduri V, Doench JG, Ksander B, Kaelin WG Jr, Haq R G protein-coupled receptors (GPCRs) constitute the largest superfamily of cell-surface receptors, yet the spatial constraints governing their signaling remain poorly defined. Here, we demonstrate that G?, an essential downstream component of GPCR signaling, undergoes a spatial shift from the plasma membrane to the endolysosomal compartment upon its constitutive activation. Using a genome-wide CRISPR screen, we identify the adaptor protein AP-3 as the essential mediator of this trafficking event. Loss of AP-3-dependent recruitment impairs G?-driven signaling and proliferation in uveal melanoma cells harboring oncogenic G? mutations. We further identify a highly evolutionarily conserved AP-3 binding motif in all G? proteins, present from yeast to humans. Disrupting this site causes G? mislocalization and potently suppresses tumor growth and metastasis in vivo. Conversely, tethering G? to the endolysosomal membrane is sufficient to rescue oncogenic signaling. Our findings reveal that endolysosomal recruitment is a fundamental, conserved requirement for G? activity, uncovering a spatial vulnerability that may be exploited to target dysregulated G-protein signaling in human disease. |
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Annals of Surgical Oncology Park KU, Sather BK, Shah A, Minami CA, Butler L, Love JA, McLean K, Dunn A, Mittendorf EA, King TA |
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Blood Advances Paolino JD, Hebert K, Yang J, Duncan CN, Lehmann LE, Kapadia M, Takahashi T, Keating AK, Alvarez-Calderon F, Burns MA, Davies K, Degar BA, Vrooman LM, Kesselheim J, Feraco AM MD, MMSc, Pikman Y, Place AE, Pollard JA, Kean LS, Neuberg DS, Baumeister SHC |
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Blood Advances Clofarabine for Relapsed/Refractory LCH and Non-LC Histiocytosis Degar BA, Friedmann AM, Jacobsen ED, Kao PC, Koch VB, London WB |
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Blood Advances Evolution of Real-World Front-Line Treatment Patterns in Multiple Myeloma Nannini K, Yildirim C, Huhmann L, Culnan JM, Corrigan JK, Do NV, Brophy MT, Munshi NC, Fillmore NR, Edwards CV |
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Breast Grinda T, Heiling HM, Tayob N, Davis R, Cotter C, DeMeo MK, Moy B, Savoie J, Mayer EL, Tolaney SM, Lin NU, Freedman RA |
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Breast Cancer Research and Treatment Tesch ME, Graham N, Snow C, Stever CE, Parker TS, Luo M, Martino IG, Drummey B, Virani S, Santos K, Bsat J, Ryan S, Hughes ME, Wrabel E, Tung N, Faggen M, Sinclair N, King TA, Mittendorf EA, Tayob N, Lin NU, Partridge AH, Tolaney SM, Garrido-Castro AC |
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Breast Cancer Research and Treatment Mayer EL |
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Cell Genomics Torlai Triglia E, Miller TE, Durand NC, Kim KL, Casaní-Galdón S, D'Antonio J, Javed N, Paz Hernandez A, Raman A, Cruz AJ, Issner R, Choudhary A, Aguet F, Verga J, Ramanathan V, Li CM, Hecht V, Hansen AS, Aryee MJ, Epstein CB, Najm FJ, Shoresh N, Ardlie K, Bernstein BE, Gaskell E |
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Cell Reports Qian Y, Panaampon J, Chapuy B, Zhang X, Zhao X, Wang Z, Zhang P, Zhang A, Ke Q, Zhong J, Yuan P, Zhang L, Hong M, Choi IK, Guan J, Rodig S, Pozdnyakova O, Wu H, Shipp MA, Dougan SK, Zhang B |
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Cell Reports Recurrent ZC3H18 Mutations Stabilize Oncogenic Endogenous Retroviral RNA Tanu T, Cox AM, Karlow JA, Sharma P, Sun K, Babu S, Roelofs MK, Jeon E, Chen J, Wu C, Brown J, Liu D, Burns KH, Insco ML |
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Clinical Cancer Research Yang Z, Bhattarai UR, Hayes MK, Partan ES, Potter A, Herbert ZT, Lane KM, Sawyer HR, Polak MM, Cheng SC, Matulonis UA, Ho Sui SJ, Konstantinopoulos PA, Hill SJ |
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Clinical Chemistry Highly Accurate Sequencing Methods for Low-Frequency Variant Detection Darbeheshti F, Narayan A, Zeggar HR, Adalsteinsson VA, Makrigiorgos GM |
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Current Biology Evolution of a Core Ribosomal Innovation in Octopus Mitra R, Han R, Scott TJ, Grearson AG, Liu CG, Kim H, Bellono NW, Lee ASY |
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ESMO Open Lee S, Peters ML, Modest AM, Keko M, Bockorny B |
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Genetics in Medicine Familial Risk Stratification Across Cancer Syndromes Using Fam3PRO Liang JW, Shannon KM, Bear LM, Guan Z, Braun D, Parmigiani G |
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JCO Oncology Practice When Systems Fail the Vulnerable: Cancer Care for Patients with Mental Illness O'Loughlin L, Leo J, Lloyd MR, Zerillo JA, Rangachari D |
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Journal of Pain and Symptom Management Insurance Type and Quality of End-of-Life Care in Adults < 65 Years with Hematologic Malignancies Raman HS, Lamp T, Abel GA, Odejide OO |
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Journal of Nuclear Medicine Ravi P, Zhong C, Perez KJ, Xie W, Volpe V, Lee GM, Boardman J, Pittard EG, Stoltenberg H, Jacene H, Weeks LD, Sperling AS |
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Journal of the American Society of Nephrology Gupta S, Sharon E, Blau JA, Leaf DE |
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Leukemia and Lymphoma Garcia JS, Chen EC, Stahl M |
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Nature Reviews Urology Escaping the Matrix: Disrupted Integrin Signalling Enables Neuroendocrine Differentiation Egelberg J, Beltran H |
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Pediatric Blood and Cancer ASSIST: Refinement of a Benefits Navigator Intervention Among Low-Income Pediatric Oncology Families Kellett J, Aziz-Bose R, Kelly CA, Wolfe J, Bona K |
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Pediatric Blood and Cancer Chevalier L, Robinson E, Weller E, Mintor R, Blacken R, Tarquini S, Warren EAH, Rosenberg AR, Lehmann LE, Zhou ES |
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Protein and Cell Netrin-1’s Unique Surface Pocket for a Potential Anti-Cancer Drug-Binding Target Wang JH |