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Dana-Farber Research Publication 10.15.2022

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October 15, 2022

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:


A MIR17HG-Derived Long Noncoding RNA Provides an Essential Chromatin Scaffold for Protein Interaction and Myeloma Growth

Morelli E, Fulciniti M, Samur MK, Wert-Lamas L, Gulla A, Aktas Samur A, Talluri S, Bianchi G, Johnstone M, Liu N, Gramegna D, Maisano D, Tai YT, Chauhan D, Hideshima T, Shammas MA, Anderson KC, Novina CD

Long noncoding RNAs (lncRNA) can drive tumorigenesis and are susceptible to therapeutic intervention. Here, we used a large-scale CRISPR interference viability screen to interrogate cell growth dependency to lncRNA genes in multiple myeloma (MM), and identified a prominent role for the miR-17-92 cluster host gene (MIR17HG). We show that a MIR17HG-derived lncRNA, named lnc-17-92, is the main mediator of cell growth dependency acting in a microRNA- and DROSHA- independent manner. Lnc-17-92 provides a chromatin scaffold for the functional interaction between c-MYC and WDR82, thus promoting the expression of ACACA, which encodes the rate-limiting enzyme of de novo lipogenesis acetyl-coA carboxylase 1 (ACC1). Targeting MIR17HG pre-RNA with clinically applicable antisense molecules disrupts the transcriptional and functional activities of lnc-17-92, causing potent anti-tumor effects both in vitro and in vivo in three pre-clinical animal models, including a clinically relevant PDX-NSG mouse model. This study establishes a novel oncogenic function of MIR17HG and provides potent inhibitors for translation to clinical trials.

Cancer Cell

MPS1 Inhibition Primes Immunogenicity of KRAS-LKB1 Mutant Lung Cancer

Kitajima S, Tani T, Springer BF, Campisi M, Haratani K, Chen M, Knelson EH, Mahadevan NR, Ritter J, Yoshida R, Köhler J, Ogino A, Sundararaman SK, Thai TC, Piel B, Kivlehan S, Obua BN, Purcell C, Barbie TU, Lizotte PH, Jänne PA, Paweletz CP, Gokhale PC, Barbie DA

KRAS-LKB1 (KL) mutant lung cancers silence STING owing to intrinsic mitochondrial dysfunction, resulting in T cell exclusion and resistance to programmed cell death (ligand) 1 (PD-[L]1) blockade. Here we discover that KL cells also minimize intracellular accumulation of 2'3'-cyclic GMP-AMP (2'3'-cGAMP) to further avoid downstream STING and STAT1 activation. An unbiased screen to co-opt this vulnerability reveals that transient MPS1 inhibition (MPS1i) potently re-engages this pathway in KL cells via micronuclei generation. This effect is markedly amplified by epigenetic de-repression of STING and only requires pulse MPS1i treatment, creating a therapeutic window compared with non-dividing cells. A single course of decitabine treatment followed by pulse MPS1i therapy restores T cell infiltration in vivo, enhances anti-PD-1 efficacy, and results in a durable response without evidence of significant toxicity.


Before You Call the Midwife

Glimcher LH, Petsko GA

The 2022 Lasker-DeBakey Clinical Medical Research Award is presented to Yuk Ming Dennis Lo of the Chinese University of Hong Kong for the discovery of fetal DNA in maternal blood, leading to development of noninvasive prenatal testing for Down syndrome.

Journal of Clinical Oncology

A Phase II, Two-Stage Study of Letrozole and Abemaciclib in Estrogen Receptor-Positive Recurrent Endometrial Cancer

Konstantinopoulos PA, Lee EK, Xiong N, Krasner C, Campos S, Kolin DL, Liu JF, Horowitz N, Wright AA, Bouberhan S, Penson RT, Yeku O, Bowes B, Needham H, Hayes M, Sawyer H, Polak M, Shea M, Cheng SC, Castro C, Matulonis UA

PURPOSE: Estrogen receptor (ER)-positive endometrial cancers (ECs) are characterized by phosphatidylinositol 3-kinase (PI3K) and receptor tyrosine kinase (RTK)/RAS/b-catenin (CTNNB1) pathway alterations in approximately 90% and 80% of cases, respectively. Extensive cross-talk between ER, PI3K, and RTK/RAS/CTNNB1 pathways leads to both ligand-dependent and ligand-independent ER transcriptional activity as well as upregulation of cyclin D1 which, in complex with cyclin-dependent kinases 4 and 6 (CDK4 and CDK6), is a critical regulator of cell cycle progression and a key mediator of resistance to hormonal therapy. We hypothesized that the combination of the aromatase inhibitor letrozole and CDK4/6 inhibitor abemaciclib would demonstrate promising activity in this setting.

METHODS: We conducted a phase II, two-stage study of letrozole/abemaciclib in recurrent ER-positive EC. Eligibility criteria included measurable disease, no limit on prior therapies, and all EC histologies; prior hormonal therapy was allowed. Primary end points were objective response rate by RECIST 1.1 and progression-free survival (PFS) rate at 6 months.

RESULTS: At the data cutoff date (December 03, 2021), 30 patients (28 with endometrioid EC) initiated protocol therapy; 15 (50%) patients had prior hormonal therapy. There were nine total responses (eight confirmed), for an objective response rate of 30% (95% CI, 14.7 to 49.4), all in endometrioid adenocarcinomas. Median PFS was 9.1 months, PFS at 6 months was 55.6% (95% CI, 35.1 to 72), and median duration of response was 7.4 months. Most common grade 3 treatment-related adverse events were neutropenia (20%) and anemia (17%). Responses were observed regardless of grade, prior hormonal therapy, mismatch repair, and progesterone receptor status. Exploratory tumor profiling revealed several mechanistically relevant candidate predictors of response (CTNNB1, KRAS, and CDKN2A mutations) or absence of response (TP53 mutations), which require independent validation.

CONCLUSION: Letrozole/abemaciclib demonstrated encouraging and durable evidence of activity in recurrent ER positive endometrioid EC.

JAMA Oncology

Differences in Cancer Phenotypes Among Frequent CHEK2 Variants and Implications for Clinical Care-Checking CHEK2

Bychkovsky BL, Agaoglu NB, Scheib R, Garber JE, Rana HQ

IMPORTANCE: Germline CHEK2 pathogenic variants (PVs) are frequently detected by multigene cancer panel testing (MGPT), but our understanding of PVs beyond c.1100del has been limited.

OBJECTIVE: To compare cancer phenotypes of frequent CHEK2 PVs individually and collectively by variant type.

DESIGN, SETTING, AND PARTICIPANTS: This retrospective cohort study was carried out in a single diagnostic testing laboratory from 2012 to 2019. Overall, 3783 participants with CHEK2 PVs identified via MGPT were included. Medical histories of cancer in participants with frequent PVs, negative MGPT (wild type), loss-of-function (LOF), and missense were compared.

MAIN OUTCOMES AND MEASURES:Participants were stratified by CHEK2 PV type. Descriptive statistics were summarized including median (IQR) for continuous variables and proportions for categorical characteristics. Differences in age and proportions were assessed with Wilcoxon rank sum and Fisher exact tests, respectively. Frequencies, odds ratios (ORs), 95% confidence intervals were calculated, and P values were corrected for multiple comparisons where appropriate.

RESULTS:Of the 3783 participants with CHEK2 PVs, 3473 (92%) were female and most reported White race. Breast cancer was less frequent in participants with p.I157T (OR, 0.66; 95% CI, 0.56-0.78; P<.001), p.S428F (OR, 0.59; 95% CI. 0.46-0.76; P<.001), and p.T476M (OR, 0.74; 95% CI, 0.56-0.98; P = .04) PVs compared with other PVs and an association with nonbreast cancers was not found. Following the exclusion of p.I157T, p.S428F, and p.T476M, participants with monoallelic CHEK2 PV had a younger age at first cancer diagnosis (P < .001) and were more likely to have breast (OR, 1.83; 95% CI, 1.66-2.02; P < .001), thyroid (OR, 1.63; 95% CI, 1.26-2.08; P < .001), and kidney cancer (OR, 2.57; 95% CI, 1.75-3.68; P < .001) than the wild-type cohort. Participants with a CHEK2 PV were less likely to have a diagnosis of colorectal cancer (OR, 0.62; 95% CI, 0.51-0.76; P < .001) compared with those in the wild-type cohort. There were no significant differences between frequent CHEK2 PVs and c.1100del and no differences between CHEK2 missense and LOF PVs.

CONCLUSIONS AND RELEVANCE:CHEK2 PVs, with few exceptions (p.I157T, p.S428F, and p.T476M), were associated with similar cancer phenotypes irrespective of variant type. CHEK2 PVs were not associated with colorectal cancer, but were associated with breast, kidney, and thyroid cancers. Compared with other CHEK2 PVs, the frequent p.I157T, p.S428F, and p.T476M alleles have an attenuated association with breast cancer and were not associated with nonbreast cancers. These data may inform the genetic counseling and care of individuals with CHEK2 PVs.

Nature Cancer

Mesenchymal and Adrenergic Cell Lineage States in Neuroblastoma Possess Distinct Immunogenic Phenotypes

Sengupta S, Das S, Crespo AC, Mahadevan NR, Campisi M, Ali AK, Sharma B, Rowe JH, Huang H, Debruyne DN, Cerda ED, Krajewska M, Dries R, Chen M, Soriano L, Romee R, Miller BC, Barbie DA, Lieberman J, George RE

Apart from the anti-GD2 antibody, immunotherapy for neuroblastoma has had limited success due to immune evasion mechanisms, coupled with an incomplete understanding of predictors of response. Here, from bulk and single-cell transcriptomic analyses, we identify a subset of neuroblastomas enriched for transcripts associated with immune activation and inhibition and show that these are predominantly characterized by gene expression signatures of the mesenchymal lineage state. By contrast, tumors expressing adrenergic lineage signatures are less immunogenic. The inherent presence or induction of the mesenchymal state through transcriptional reprogramming or therapy resistance is accompanied by innate and adaptive immune gene activation through epigenetic remodeling. Mesenchymal lineage cells promote T cell infiltration by secreting inflammatory cytokines, are efficiently targeted by cytotoxic T and natural killer cells and respond to immune checkpoint blockade. Together, we demonstrate that distinct immunogenic phenotypes define the divergent lineage states of neuroblastoma and highlight the immunogenic potential of the mesenchymal lineage.

Nature Communications

Author Correction: Identification of Optimal Dosing Schedules of Dacomitinib and Osimertinib for A Phase I/II Trial in Advanced EGFR-Mutant Non-Small Cell Lung Cancer

Poels KE, Frisco-Cabanos H, Chakrabarti S, Napoli C, McDonald TO, Hata A, Michor F

The original version of this Article contained an error in Fig. 1b, in which the mathematics were replaced by random symbols. In addition, the original version of this Article contained an error in Fig. 4, in which the shading representing predictions and interquartile ranges from mathematical modelling predictions was missing. This has been corrected in both the PDF and HTML versions of the Article.

Nature Communications

Genomic and Biological Study of Fusion Genes as Resistance Mechanisms to EGFR Inhibitors

Kobayashi Y, Oxnard GR, Cohen EF, Mahadevan NR, Alessi JV, Hung YP, Bertram AA, Blasco RB, Li J, Nguyen T, Voligny E, Ananda G, Chiarle R, Tolstorukov MY, Sholl LM, Jänne PA

The clinical significance of gene fusions detected by DNA-based next generation sequencing remains unclear as resistance mechanisms to EGFR tyrosine kinase inhibitors in EGFR mutant non-small cell lung cancer. By studying EGFR inhibitor-resistant patients treated with a combination of an EGFR inhibitor and a drug targeting the putative resistance-causing fusion oncogene, we identify patients who benefit and those who do not from this treatment approach. Through evaluation including RNA-seq of potential drug resistance-imparting fusion oncogenes in 504 patients with EGFR mutant lung cancer, we identify only a minority of them as functional, potentially capable of imparting EGFR inhibitor resistance. We further functionally validate fusion oncogenes in vitro using CRISPR-based editing of EGFR mutant cell lines and use these models to identify known and unknown drug resistance mechanisms to combination therapies. Collectively, our results partially reveal the complex nature of fusion oncogenes as potential drug resistance mechanisms and highlight approaches that can be undertaken to determine their functional significance.

New England Journal of Medicine

Adagrasib in Non-Small-Cell Lung Cancer Reply

Jänne PA

Jänne et al. (July 14 issue) report the results of a phase 2 study of adagrasib involving patients with KRASG12C-mutated non–small-cell lung cancer (NSCLC). In a post hoc evaluation for intracranial response, the authors highlight a confirmed objective response rate of 33.3% among 33 patients. These patients had previously treated, stable central nervous system (CNS) metastases, and 81.8% of the patients had received radiation therapy before adagrasib treatment (59% within 3 months before study entry and 37% at least 6 months before study entry).

ACS Chemical Biology

Redirecting the Neo-Substrate Specificity of Cereblon-Targeting PROTACs to Helios

Verano AL, Donovan KA, Mageed N, Yue H, Nowak RP, Fischer ES

Annals of Surgical Oncology

Screening MRI Does Not Increase Cancer Detection or Result in an Earlier Stage at Diagnosis for Patients with High-Risk Breast Lesions: A Propensity Score Analysis

Laws A, Katlin F, Hans M, Graichen M, Kantor O, Minami C, Bychkovsky BL, Pace LE, Scheib R, Garber JE, King TA

Biophysical Journal

Collective Polymerase Dynamics Emerge from DNA Supercoiling During Transcription

Sevier SA, Hormoz S

Blood Advances

Virtual Frailty Assessment for Older Adults with Hematologic Malignancies

DuMontier C, Jaung T, Bahl NE, Manor B, Testa M, Dieli-Conwright CM, Kim D, Hshieh T, Driver JA, Abel GA

Blood Advances

Patient Perspectives on Testing for Clonal Hematopoiesis of Indeterminate Potential

Sella T, Fell GG, Miller PG, Gibson CJ, Snow C, Peppercorn JM, Come SE, Frank E, Neuberg D, Ebert BL, Partridge AH

British Journal of Cancer

Concurrent Inhibition of CDK2 Adds to the Anti-Tumour Activity of CDK4/6 Inhibition in GIST

Schaefer IM, Hemming ML, Lundberg MZ, Serrata MP, Goldaracena I, Liu N, Yin P, Paulo JA, Gygi SP, George S, Morgan JA, Bertagnolli MM, Sicinska ET, Chu C, Zheng S, Mariño-Enriquez A, Hornick JL, Raut CP, Ou WB, Demetri GD, Saka SK, Fletcher JA

British Journal of Haematology

Daratumumab Plus Lenalidomide, Bortezomib and Dexamethasone in Newly Diagnosed Multiple Myeloma: Analysis of Vascular Thrombotic Events in the GRIFFIN Study

Laubach J, Richardson PG

Clinical Cancer Research

Neoadjuvant Chemotherapy is Associated with Altered Immune Cell Infiltration and an Anti-Tumorigenic Microenvironment in Resected Pancreatic Cancer

Dias Costa A, Väyrynen SA, Zhang J, Lau MC, Williams HL, Yuan C, Morales-Oyarvide V, Elganainy D, Singh H, Cleary JM, Perez K, Ng K, Freed-Pastor W, Mancias JD, Dougan SK, Wang J, Rubinson DA, Brais L, Reilly E, Clancy T, Aguirre A, Wolpin BM, Nowak JA

Diagnostic and Interventional Imaging

The BUMPy Road of Peritoneal Metastases in Ovarian Cancer

Worley M, Shinagare AB

Expert Opinion on Pharmacotherapy

Current Therapeutic Options for Glioblastoma and Future Perspectives

Aquilanti E, Wen PY

Journal of Geriatric Oncology

'ADVANCE' (A Pilot Trial) ADjuVANt Chemotherapy in the Elderly: Developing and Evaluating Lower-Toxicity Chemotherapy Options for Older Patients with Breast Cancer

Freedman RA, Li T, Tayob N, Faggen MG, Sinclair NF, Chen WY, Parsons HA, Mayer EL, Lange PB, Basta AS, Perilla-Glen A, Lederman RI, McAllister SS, Mittendorf EA, Miller PG, Gibson CJ, Burstein HJ

Journal of Medical Virology

Anti-SARS-CoV-2 Activity of Targeted Kinase Inhibitors: Repurposing Clinically Available Drugs for COVID-19 Therapy

Slabicki M, Patten JJ, Zou C, Meng C, Wang J, Nowak RP, Yang PL, Sattler M, Stone RM, Griffin JD, Gray NS, Gummuluru S, Weisberg E

Lung Cancer

Safety of Image Guided Research Biopsies in Patients with Thoracic Malignancies

Soosman SK, Schenker MP, Mazzola E, Voligny E, Smokovich A, Bay C, Nguyen T, Michael K, Jänne PA, Rabin M, Glazer DI, Johnson BE, Luo J


Randomized Phase II Trial of Sapanisertib ± TAK-117 vs. Everolimus in Patients with Advanced Renal Cell Carcinoma After VEGF-Targeted Therapy

Choueiri T

STAR Protocols

Analysis of Germline-Driven Ancestry-Associated Gene Expression in Cancers

Beroukhim R, Cherniack AD

Trends in Cancer

GOT2 Consider the Tumor Microenvironment

Vander Heiden MG


Immune Evasion of SARS-CoV-2 Omicron Subvariants

Ke H, Chang MR, Marasco WA