bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from Atypical KRASG12R Mutant Is Impaired in PI3K Signaling and Macropinocytosis in Pancreatic Cancer
Authors: Hobbs G. Aaron , Baker Nicole M. , Miermont Anne M. , Thurman Ryan D. , Pierobon Mariaelena , Tran Timothy H. , Anderson Andrew O. , Waters Andrew M. , Diehl J. Nathaniel , Papke Bjoern , Hodge Richard G. , Klomp Jennifer E. , Goodwin Craig M. , DeLiberty Jonathan M. , Wang Junning , Ng Raymond W.S. , Gautam Prson , Bryant Kirsten L. , Esposito Dominic , Campbell Sharon L. , Petricoin Emanuel F. , Simanshu Dhirendra K. , Aguirre Andrew J. , Wolpin Brian M. , Wennerberg Krister , Rudloff Udo , Cox Adrienne D. , Der Channing J.
Published: March 2024

Abstract
Allele-specific signaling by different KRAS alleles remains poorly understood. The KRASG12R mutation displays uneven prevalence among cancers that harbor the highest occurrence of KRAS mutations: It is rare (∼1%) in lung and colorectal cancers, yet relatively common (∼20%) in pancreatic ductal adenocarcinoma (PDAC), suggesting context-specific properties. We evaluated whether KRASG12R is functionally distinct from the more common KRASG12D- or KRASG12V-mutant proteins (KRASG12D/V). We found that KRASG12D/V but not KRASG12R drives macropinocytosis and that MYC is essential for macropinocytosis in KRASG12D/V- but not KRASG12R-mutant PDAC. Surprisingly, we found that KRASG12R is defective for interaction with a key effector, p110α PI3K (PI3Kα), due to structural perturbations in switch II. Instead, upregulated KRAS-independent PI3Kγ activity was able to support macropinocytosis in KRASG12R-mutant PDAC. Finally, we determined that KRASG12R-mutant PDAC displayed a distinct drug sensitivity profile compared with KRASG12D-mutant PDAC but is still responsive to the combined inhibition of ERK and autophagy.
Significance:
We determined that KRASG12R is impaired in activating a key effector, p110α PI3K. As such, KRASG12R is impaired in driving macropinocytosis. However, overexpression of PI3Kγ in PDAC compensates for this deficiency, providing one basis for the prevalence of this otherwise rare KRAS mutant in pancreatic cancer but not other cancers.

See related commentary by Falcomatà et al., p. 23.

This article is highlighted in the In This Issue feature, p. 1
Data from Personalized Antibodies for Gastroesophageal Adenocarcinoma (PANGEA): A Phase II Study Evaluating an Individualized Treatment Strategy for Metastatic Disease
Authors: Catenacci Daniel V.T. , Moya Stephanie , Lomnicki Samantha , Chase Leah M. , Peterson Bryan F. , Reizine Natalie , Alpert Lindsay , Setia Namrata , Xiao Shu-Yuan , Hart John , Siddiqui Uzma D. , Hogarth D. Kyle , Eng Oliver S. , Turaga Kiran , Roggin Kevin , Posner Mitchell C. , Chang Paul , Narula Sunil , Rampurwala Murtuza , Ji Yuan , Karrison Theodore , Liao Chih-Yi , Polite Blase N. , Kindler Hedy L.
Published: March 2024

Abstract
The one-year and median overall survival (mOS) rates of advanced gastroesophageal adenocarcinomas (GEA) are ∼50% and <12 months, respectively. Baseline spatial and temporal molecular heterogeneity of targetable alterations may be a cause of failure of targeted/immunooncologic therapies. This heterogeneity, coupled with infrequent incidence of some biomarkers, has resulted in stalled therapeutic progress. We hypothesized that a personalized treatment strategy, applied at first diagnosis then serially over up to three treatment lines using monoclonal antibodies combined with optimally sequenced chemotherapy, could contend with these hurdles. This was tested using a novel clinical expansion-platform type II design with a survival primary endpoint. Of 68 patients by intention-to-treat, the one-year survival rate was 66% and mOS was 15.7 months, meeting the primary efficacy endpoint (one-sided P = 0.0024). First-line response rate (74%), disease control rate (99%), and median progression-free survival (8.2 months) were superior to historical controls. The PANGEA strategy led to improved outcomes warranting a larger randomized study.
Significance:
This study highlights excellent outcomes achieved by individually optimizing chemotherapy, biomarker profiling, and matching of targeted therapies at baseline and over time for GEA. Testing a predefined treatment strategy resulted in improved outcomes versus historical controls. Therapeutic resistance observed in correlative analyses suggests that dual targeted inhibition may be beneficial.

This article is highlighted in the In This Issue feature, p. 211
Data from Tumor Mutational Burden as a Predictive Biomarker in Solid Tumors
Authors: Sha Dan , Jin Zhaohui , Budczies Jan , Kluck Klaus , Stenzinger Albrecht , Sinicrope Frank A.
Published: March 2024

Abstract
Tumor mutational burden (TMB), defined as the number of somatic mutations per megabase of interrogated genomic sequence, varies across malignancies. Panel sequencing–based estimates of TMB have largely replaced whole-exome sequencing–derived TMB in the clinic. Retrospective evidence suggests that TMB can predict the efficacy of immune checkpoint inhibitors, and data from KEYNOTE-158 led to the recent FDA approval of pembrolizumab for the TMB-high tumor subgroup. Unmet needs include prospective validation of TMB cutoffs in relationship to tumor type and patient outcomes. Furthermore, standardization and harmonization of TMB measurement across test platforms are important to the successful implementation of TMB in clinical practice.
Significance:
Evaluation of TMB as a predictive biomarker creates the need to harmonize panel-based TMB estimation and standardize its reporting. TMB can improve the predictive accuracy for immunotherapy outcomes, and has the potential to expand the candidate pool of patients for treatment with immune checkpoint inhibitors.
Data from MAIT Cells Promote Tumor Initiation, Growth, and Metastases via Tumor MR1
Authors: Yan Juming , Allen Stacey , McDonald Elizabeth , Das Indrajit , Mak Jeffrey Y.W. , Liu Ligong , Fairlie David P. , Meehan Bronwyn S. , Chen Zhenjun , Corbett Alexandra J. , Varelias Antiopi , Smyth Mark J. , Teng Michele W.L.
Published: March 2024

Abstract
Mucosal-associated invariant T (MAIT) cells are innate-like T cells that require MHC class I–related protein 1 (MR1) for their development. The role of MAIT cells in cancer is unclear, and to date no study has evaluated these cells in vivo in this context. Here, we demonstrated that tumor initiation, growth, and experimental lung metastasis were significantly reduced in Mr1−/− mice, compared with wild-type mice. The antitumor activity observed in Mr1−/− mice required natural killer (NK) and/or CD8+ T cells and IFNγ. Adoptive transfer of MAIT cells into Mr1−/− mice reversed metastasis reduction. Similarly, MR1-blocking antibodies decreased lung metastases and suppressed tumor growth. Following MR1 ligand exposure, some, but not all, mouse and human tumor cell lines upregulated MR1. Pretreatment of tumor cells with the stimulatory ligand 5-OP-RU or inhibitory ligand Ac-6-FP increased or decreased lung metastases, respectively. MR1-deleted tumors resulted in fewer metastases compared with parental tumor cells. MAIT cell suppression of NK-cell effector function was tumor-MR1–dependent and partially required IL17A. Our studies indicate that MAIT cells display tumor-promoting function by suppressing T and/or NK cells and that blocking MR1 may represent a new therapeutic strategy for cancer immunotherapy.
Significance:
Contradicting the perception that MAIT cells kill tumor cells, here MAIT cells promoted tumor initiation, growth, and metastasis. MR1-expressing tumor cells activated MAIT cells to reduce NK-cell effector function, partly in a host IL17A–dependent manner. MR1-blocking antibodies reduced tumor metastases and growth, and may represent a new class of cancer therapeutics.

This article is highlighted in the In This Issue feature, p. 1
Data from Inhibition of Nuclear Pore Complex Formation Selectively Induces Cancer Cell Death
Authors: Sakuma Stephen , Raices Marcela , Borlido Joana , Guglielmi Valeria , Zhu Ethan Y.S. , D'Angelo Maximiliano A.
Published: March 2024

Abstract
Nuclear pore complexes (NPC) are the central mediators of nucleocytoplasmic transport. Increasing evidence shows that many cancer cells have increased numbers of NPCs and become addicted to the nuclear transport machinery. How reducing NPC numbers affects the physiology of normal and cancer cells and whether it could be exploited for cancer therapies has not been investigated. We report that inhibition of NPC formation, a process mostly restricted to proliferating cells, causes selective cancer cell death, prevents tumor growth, and induces tumor regression. Although cancer cells die in response to NPC assembly inhibition, normal cells undergo a reversible cell-cycle arrest that allows them to survive. Mechanistically, reducing NPC numbers results in multiple alterations contributing to cancer cell death, including abnormalities in nuclear transport, catastrophic alterations in gene expression, and the selective accumulation of DNA damage. Our findings uncover the NPC formation process as a novel targetable pathway in cancer cells.
Significance:
Reducing NPC numbers in cancer cells induces death, prevents tumor growth, and results in tumor regression. Conversely, normal cells undergo a reversible cell-cycle arrest in response to inhibition of NPC assembly. These findings expose the potential of targeting NPC formation in cancer.

This article is highlighted in the In This Issue feature, p. 1
Data from A First-in-Human Study and Biomarker Analysis of NKTR-214, a Novel IL2Rβγ-Biased Cytokine, in Patients with Advanced or Metastatic Solid Tumors
Authors: Bentebibel Salah-Eddine , Hurwitz Michael E. , Bernatchez Chantale , Haymaker Cara , Hudgens Courtney W. , Kluger Harriet M. , Tetzlaff Michael T. , Tagliaferri Mary A. , Zalevsky Jonathan , Hoch Ute , Fanton Christie , Aung Sandra , Hwu Patrick , Curti Brendan D. , Tannir Nizar M. , Sznol Mario , Diab Adi
Published: March 2024

Abstract
NKTR-214 (bempegaldesleukin) is a novel IL2 pathway agonist, designed to provide sustained signaling through heterodimeric IL2 receptor βγ to drive increased proliferation and activation of CD8+ T and natural killer cells without unwanted expansion of T regulatory cells (Treg) in the tumor microenvironment. In this first-in-human multicenter phase I study, NKTR-214 administered as an outpatient regimen was well tolerated and showed clinical activity including tumor shrinkage and durable disease stabilization in heavily pretreated patients. Immune activation and increased numbers of immune cells were observed in the periphery across all doses and cycles with no loss of NKTR-214 activity with repeated administration. On-treatment tumor biopsies demonstrated that NKTR-214 promoted immune cell increase with limited increase of Tregs. Transcriptional analysis of tumor biopsies showed that NKTR-214 engaged the IL2 receptor pathway and significantly increased genes associated with an effector phenotype. Based on safety and pharmacodynamic markers, the recommended phase II dose was determined to be 0.006 mg/kg every three weeks.
Significance:
We believe that IL2- and IL2 pathway–targeted agents such as NKTR-214 are key components to an optimal immunotherapy treatment algorithm. Based on its biological activity and tolerability, NKTR-214 is being studied with approved immuno-oncology agents including checkpoint inhibitors.

See related commentary by Sullivan, p. 694.

This article is highlighted in the In This Issue feature, p. 681
Data from Oral Mucosal Organoids as a Potential Platform for Personalized Cancer Therapy
Authors: Driehuis Else , Kolders Sigrid , Spelier Sacha , Lõhmussaar Kadi , Willems Stefan M. , Devriese Lot A. , de Bree Remco , de Ruiter Emma J. , Korving Jeroen , Begthel Harry , van Es Johan H. , Geurts Veerle , He Gui-Wei , van Jaarsveld Richard H. , Oka Rurika , Muraro Mauro J. , Vivié Judith , Zandvliet Maurice M.J.M. , Hendrickx Antoni P.A. , Iakobachvili Nino , Sridevi Priya , Kranenburg Onno , van Boxtel Ruben , Kops Geert J.P.L. , Tuveson David A. , Peters Peter J. , van Oudenaarden Alexander , Clevers Hans
Published: March 2024

Abstract
Previous studies have described that tumor organoids can capture the diversity of defined human carcinoma types. Here, we describe conditions for long-term culture of human mucosal organoids. Using this protocol, a panel of 31 head and neck squamous cell carcinoma (HNSCC)–derived organoid lines was established. This panel recapitulates genetic and molecular characteristics previously described for HNSCC. Organoids retain their tumorigenic potential upon xenotransplantation. We observe differential responses to a panel of drugs including cisplatin, carboplatin, cetuximab, and radiotherapy in vitro. Additionally, drug screens reveal selective sensitivity to targeted drugs that are not normally used in the treatment of patients with HNSCC. These observations may inspire a personalized approach to the management of HNSCC and expand the repertoire of HNSCC drugs.
Significance:
This work describes the culture of organoids derived from HNSCC and corresponding normal epithelium. These tumoroids recapitulate the disease genetically, histologically, and functionally. In vitro drug screening of tumoroids reveals responses to therapies both currently used in the treatment of HNSCC and those not (yet) used in clinical practice.

See related commentary by Hill and D'Andrea, p. 828.

This article is highlighted in the In This Issue feature, p. 813
Data from Clinical Portrait of the SARS-CoV-2 Epidemic in European Patients with Cancer
Authors: Pinato David J. , Zambelli Alberto , Aguilar-Company Juan , Bower Mark , Sng Christopher C.T. , Salazar Ramon , Bertuzzi Alexia , Brunet Joan , Mesia Ricard , Seguí Elia , Biello Federica , Generali Daniele , Grisanti Salvatore , Rizzo Gianpiero , Libertini Michela , Maconi Antonio , Harbeck Nadia , Vincenzi Bruno , Bertulli Rossella , Ottaviani Diego , Carbó Anna , Bruna Riccardo , Benafif Sarah , Marrari Andrea , Wuerstlein Rachel , Carmona-Garcia M. Carmen , Chopra Neha , Tondini Carlo , Mirallas Oriol , Tovazzi Valeria , Betti Marta , Provenzano Salvatore , Fotia Vittoria , Cruz Claudia Andrea , Dalla Pria Alessia , D'Avanzo Francesca , Evans Joanne S. , Saoudi-Gonzalez Nadia , Felip Eudald , Galazi Myria , Garcia-Fructuoso Isabel , Lee Alvin J.X. , Newsom-Davis Thomas , Patriarca Andrea , García-Illescas David , Reyes Roxana , Dileo Palma , Sharkey Rachel , Wong Yien Ning Sophia , Ferrante Daniela , Marco-Hernández Javier , Sureda Anna , Maluquer Clara , Ruiz-Camps Isabel , Gaidano Gianluca , Rimassa Lorenza , Chiudinelli Lorenzo , Izuzquiza Macarena , Cabirta Alba , Franchi Michela , Santoro Armando , Prat Aleix , Tabernero Josep , Gennari Alessandra , Avanzi Gian Carlo , Bellan Mattia , Castello Luigi Mario , Martinez Maria , Mollà Meritxell , Pirisi Mario , Scotti Lorenza , Swallow Judith
Published: March 2024

Abstract
The SARS-CoV-2 pandemic significantly affected oncology practice across the globe. There is uncertainty as to the contribution of patients' demographics and oncologic features to severity and mortality from COVID-19 and little guidance as to the role of anticancer and anti–COVID-19 therapy in this population. In a multicenter study of 890 patients with cancer with confirmed COVID-19, we demonstrated a worsening gradient of mortality from breast cancer to hematologic malignancies and showed that male gender, older age, and number of comorbidities identify a subset of patients with significantly worse mortality rates from COVID-19. Provision of chemotherapy, targeted therapy, or immunotherapy did not worsen mortality. Exposure to antimalarials was associated with improved mortality rates independent of baseline prognostic factors. This study highlights the clinical utility of demographic factors for individualized risk stratification of patients and supports further research into emerging anti–COVID-19 therapeutics in SARS-CoV-2–infected patients with cancer.
Significance:
In this observational study of 890 patients with cancer diagnosed with SARS-CoV-2, mortality was 33.6% and predicted by male gender, age ≥65, and comorbidity burden. Delivery of cancer therapy was not detrimental to severity or mortality from COVID-19. These patients should be the focus of shielding efforts during the SARS-CoV-2 pandemic.

This article is highlighted in the In This Issue feature, p. 1426
Data from Machine-Learning and Chemicogenomics Approach Defines and Predicts Cross-Talk of Hippo and MAPK Pathways
Authors: Pham Trang H. , Hagenbeek Thijs J. , Lee Ho-June , Li Jason , Rose Christopher M. , Lin Eva , Yu Mamie , Martin Scott E. , Piskol Robert , Lacap Jennifer A. , Sampath Deepak , Pham Victoria C. , Modrusan Zora , Lill Jennie R. , Klijn Christiaan , Malek Shiva , Chang Matthew T. , Dey Anwesha
Published: March 2024

Abstract
Hippo pathway dysregulation occurs in multiple cancers through genetic and nongenetic alterations, resulting in translocation of YAP to the nucleus and activation of the TEAD family of transcription factors. Unlike other oncogenic pathways such as RAS, defining tumors that are Hippo pathway–dependent is far more complex due to the lack of hotspot genetic alterations. Here, we developed a machine-learning framework to identify a robust, cancer type–agnostic gene expression signature to quantitate Hippo pathway activity and cross-talk as well as predict YAP/TEAD dependency across cancers. Further, through chemical genetic interaction screens and multiomics analyses, we discover a direct interaction between MAPK signaling and TEAD stability such that knockdown of YAP combined with MEK inhibition results in robust inhibition of tumor cell growth in Hippo dysregulated tumors. This multifaceted approach underscores how computational models combined with experimental studies can inform precision medicine approaches including predictive diagnostics and combination strategies.
Significance:
An integrated chemicogenomics strategy was developed to identify a lineage-independent signature for the Hippo pathway in cancers. Evaluating transcriptional profiles using a machine-learning method led to identification of a relationship between YAP/TAZ dependency and MAPK pathway activity. The results help to nominate potential combination therapies with Hippo pathway inhibition.

This article is highlighted in the In This Issue feature, p. 521
Data from The Lipogenic Regulator SREBP2 Induces Transferrin in Circulating Melanoma Cells and Suppresses Ferroptosis
Authors: Hong Xin , Roh Whijae , Sullivan Ryan J. , Wong Keith H.K. , Wittner Ben S. , Guo Hongshan , Dubash Taronish D. , Sade-Feldman Moshe , Wesley Benjamin , Horwitz Elad , Boland Genevieve M. , Marvin Dieuwke L. , Bonesteel Todd , Lu Chenyue , Aguet François , Burr Risa , Freeman Samuel S. , Parida Laxmi , Calhoun Katherine , Jewett Michelle K. , Nieman Linda T. , Hacohen Nir , Näär Anders M. , Ting David T. , Toner Mehmet , Stott Shannon L. , Getz Gad , Maheswaran Shyamala , Haber Daniel A.
Published: March 2024

Abstract
Circulating tumor cells (CTC) are shed by cancer into the bloodstream, where a viable subset overcomes oxidative stress to initiate metastasis. We show that single CTCs from patients with melanoma coordinately upregulate lipogenesis and iron homeostasis pathways. These are correlated with both intrinsic and acquired resistance to BRAF inhibitors across clonal cultures of BRAF-mutant CTCs. The lipogenesis regulator SREBP2 directly induces transcription of the iron carrier Transferrin (TF), reducing intracellular iron pools, reactive oxygen species, and lipid peroxidation, thereby conferring resistance to inducers of ferroptosis. Knockdown of endogenous TF impairs tumor formation by melanoma CTCs, and their tumorigenic defects are partially rescued by the lipophilic antioxidants ferrostatin-1 and vitamin E. In a prospective melanoma cohort, presence of CTCs with high lipogenic and iron metabolic RNA signatures is correlated with adverse clinical outcome, irrespective of treatment regimen. Thus, SREBP2-driven iron homeostatic pathways contribute to cancer progression, drug resistance, and metastasis.
Significance:
Through single-cell analysis of primary and cultured melanoma CTCs, we have uncovered intrinsic cancer cell heterogeneity within lipogenic and iron homeostatic pathways that modulates resistance to BRAF inhibitors and to ferroptosis inducers. Activation of these pathways within CTCs is correlated with adverse clinical outcome, pointing to therapeutic opportunities.

This article is highlighted in the In This Issue feature, p. 521
Data from Poor Survival and Differential Impact of Genetic Features of Black Patients with Acute Myeloid Leukemia
Authors: Bhatnagar Bhavana , Kohlschmidt Jessica , Mrózek Krzysztof , Zhao Qiuhong , Fisher James L. , Nicolet Deedra , Walker Christopher J. , Mims Alice S. , Oakes Christopher , Giacopelli Brian , Orwick Shelley , Boateng Isaiah , Blachly James S. , Maharry Sophia E. , Carroll Andrew J. , Powell Bayard L. , Kolitz Jonathan E. , Stone Richard M. , Byrd John C. , Paskett Electra D. , de la Chapelle Albert , Garzon Ramiro , Eisfeld Ann-Kathrin
Published: March 2024

Abstract
Clinical outcome of patients with acute myeloid leukemia (AML) is associated with cytogenetic and molecular factors and patient demographics (e.g., age and race). We compared survival of 25,523 non-Hispanic Black and White adults with AML using Surveillance Epidemiology and End Results (SEER) Program data and performed mutational profiling of 1,339 patients with AML treated on frontline Alliance for Clinical Trials in Oncology (Alliance) protocols. Black patients had shorter survival than White patients, both in SEER and in the setting of Alliance clinical trials. The disparity was especially pronounced in Black patients <60 years, after adjustment for socioeconomic (SEER) and molecular (Alliance) factors. Black race was an independent prognosticator of poor survival. Gene mutation profiles showed fewer NPM1 and more IDH2 mutations in younger Black patients. Overall survival of younger Black patients was adversely affected by IDH2 mutations and FLT3-ITD, but, in contrast to White patients, was not improved by NPM1 mutations.
Significance:
We show that young Black patients have not benefited as much as White patients from recent progress in AML treatment in the United States. Our data suggest that both socioeconomic factors and differences in disease biology contribute to the survival disparity and need to be urgently addressed.

See related commentary by Vyas, p. 540.

This article is highlighted in the In This Issue feature, p. 521
Data from An Empirical Antigen Selection Method Identifies Neoantigens That Either Elicit Broad Antitumor T-cell Responses or Drive Tumor Growth
Authors: Lam Hubert , McNeil Lisa K. , Starobinets Hanna , DeVault Victoria L. , Cohen Roger B. , Twardowski Przemyslaw , Johnson Melissa L. , Gillison Maura L. , Stein Mark N. , Vaishampayan Ulka N. , DeCillis Arthur P. , Foti James J. , Vemulapalli Vijetha , Tjon Emily , Ferber Kyle , DeOliveira Daniel B. , Broom Wendy , Agnihotri Parul , Jaffee Elizabeth M. , Wong Kwok-Kin , Drake Charles G. , Carroll Pamela M. , Davis Thomas A. , Flechtner Jessica Baker
Published: March 2024

Abstract
Neoantigens are critical targets of antitumor T-cell responses. The ATLAS bioassay was developed to identify neoantigens empirically by expressing each unique patient-specific tumor mutation individually in Escherichia coli, pulsing autologous dendritic cells in an ordered array, and testing the patient's T cells for recognition in an overnight assay. Profiling of T cells from patients with lung cancer revealed both stimulatory and inhibitory responses to individual neoantigens. In the murine B16F10 melanoma model, therapeutic immunization with ATLAS-identified stimulatory neoantigens protected animals, whereas immunization with peptides associated with inhibitory ATLAS responses resulted in accelerated tumor growth and abolished efficacy of an otherwise protective vaccine. A planned interim analysis of a clinical study testing a poly-ICLC adjuvanted personalized vaccine containing ATLAS-identified stimulatory neoantigens showed that it is well tolerated. In an adjuvant setting, immunized patients generated both CD4+ and CD8+ T-cell responses, with immune responses to 99% of the vaccinated peptide antigens.
Significance:
Predicting neoantigens in silico has progressed, but empirical testing shows that T-cell responses are more nuanced than straightforward MHC antigen recognition. The ATLAS bioassay screens tumor mutations to uncover preexisting, patient-relevant neoantigen T-cell responses and reveals a new class of putatively deleterious responses that could affect cancer immunotherapy design.

This article is highlighted in the In This Issue feature, p. 521
Data from Clonal Selection with RAS Pathway Activation Mediates Secondary Clinical Resistance to Selective FLT3 Inhibition in Acute Myeloid Leukemia
Authors: McMahon Christine M. , Ferng Timothy , Canaani Jonathan , Wang Eunice S. , Morrissette Jennifer J.D. , Eastburn Dennis J. , Pellegrino Maurizio , Durruthy-Durruthy Robert , Watt Christopher D. , Asthana Saurabh , Lasater Elisabeth A. , DeFilippis RosaAnna , Peretz Cheryl A.C. , McGary Lisa H.F. , Deihimi Safoora , Logan Aaron C. , Luger Selina M. , Shah Neil P. , Carroll Martin , Smith Catherine C. , Perl Alexander E.
Published: March 2024

Abstract
Gilteritinib is a potent and selective FLT3 kinase inhibitor with single-agent clinical efficacy in relapsed/refractory FLT3-mutated acute myeloid leukemia (AML). In this context, however, gilteritinib is not curative, and response duration is limited by the development of secondary resistance. To evaluate resistance mechanisms, we analyzed baseline and progression samples from patients treated on clinical trials of gilteritinib. Targeted next-generation sequencing at the time of AML progression on gilteritinib identified treatment-emergent mutations that activate RAS/MAPK pathway signaling, most commonly in NRAS or KRAS. Less frequently, secondary FLT3-F691L gatekeeper mutations or BCR–ABL1 fusions were identified at progression. Single-cell targeted DNA sequencing revealed diverse patterns of clonal selection and evolution in response to FLT3 inhibition, including the emergence of RAS mutations in FLT3-mutated subclones, the expansion of alternative wild-type FLT3 subclones, or both patterns simultaneously. These data illustrate dynamic and complex changes in clonal architecture underlying response and resistance to mutation-selective tyrosine kinase inhibitor therapy in AML.
Significance:
Comprehensive serial genotyping of AML specimens from patients treated with the selective FLT3 inhibitor gilteritinib demonstrates that complex, heterogeneous patterns of clonal selection and evolution mediate clinical resistance to tyrosine kinase inhibition in FLT3-mutated AML. Our data support the development of combinatorial targeted therapeutic approaches for advanced AML.

See related commentary by Wei and Roberts, p. 998.

This article is highlighted in the In This Issue feature, p. 983
Data from Combination Olaparib and Temozolomide in Relapsed Small-Cell Lung Cancer
Authors: Farago Anna F. , Yeap Beow Y. , Stanzione Marcello , Hung Yin P. , Heist Rebecca S. , Marcoux J. Paul , Zhong Jun , Rangachari Deepa , Barbie David A. , Phat Sarah , Myers David T. , Morris Robert , Kem Marina , Dubash Taronish D. , Kennedy Elizabeth A. , Digumarthy Subba R. , Sequist Lecia V. , Hata Aaron N. , Maheswaran Shyamala , Haber Daniel A. , Lawrence Michael S. , Shaw Alice T. , Mino-Kenudson Mari , Dyson Nicholas J. , Drapkin Benjamin J.
Published: March 2024

Abstract
Small-cell lung cancer (SCLC) is an aggressive malignancy in which inhibitors of PARP have modest single-agent activity. We performed a phase I/II trial of combination olaparib tablets and temozolomide (OT) in patients with previously treated SCLC. We established a recommended phase II dose of olaparib 200 mg orally twice daily with temozolomide 75 mg/m2 daily, both on days 1 to 7 of a 21-day cycle, and expanded to a total of 50 patients. The confirmed overall response rate was 41.7% (20/48 evaluable); median progression-free survival was 4.2 months [95% confidence interval (CI), 2.8–5.7]; and median overall survival was 8.5 months (95% CI, 5.1–11.3). Patient-derived xenografts (PDX) from trial patients recapitulated clinical OT responses, enabling a 32-PDX coclinical trial. This revealed a correlation between low basal expression of inflammatory-response genes and cross-resistance to both OT and standard first-line chemotherapy (etoposide/platinum). These results demonstrate a promising new therapeutic strategy in SCLC and uncover a molecular signature of those tumors most likely to respond.
Significance:
We demonstrate substantial clinical activity of combination olaparib/temozolomide in relapsed SCLC, revealing a promising new therapeutic strategy for this highly recalcitrant malignancy. Through an integrated coclinical trial in PDXs, we then identify a molecular signature predictive of response to OT, and describe the common molecular features of cross-resistant SCLC.

See related commentary by Pacheco and Byers, p. 1340.

This article is highlighted in the In This Issue feature, p. 1325
Data from Resistance to Avapritinib in PDGFRA-Driven GIST Is Caused by Secondary Mutations in the PDGFRA Kinase Domain
Authors: Grunewald Susanne , Klug Lillian R. , Mühlenberg Thomas , Lategahn Jonas , Falkenhorst Johanna , Town Ajia , Ehrt Christiane , Wardelmann Eva , Hartmann Wolfgang , Schildhaus Hans-Ulrich , Treckmann Juergen , Fletcher Jonathan A. , Jung Sascha , Czodrowski Paul , Miller Stephen , Schmidt-Kittler Oleg , Rauh Daniel , Heinrich Michael C. , Bauer Sebastian
Published: March 2024

Abstract
Gastrointestinal stromal tumors (GIST) harboring activating mutations of PDGFRA respond to imatinib, with the notable exception of the most common mutation, D842V. Avapritinib is a novel, potent KIT/PDGFRA inhibitor with substantial clinical activity in patients with the D842V genotype. To date, only a minority of PDGFRA-mutant patients treated with avapritinib have developed secondary resistance. Tumor and plasma biopsies in 6 of 7 patients with PDGFRA primary mutations who progressed on avapritinib or imatinib had secondary resistance mutations within PDGFRA exons 13, 14, and 15 that interfere with avapritinib binding. Secondary PDGFRA mutations causing V658A, N659K, Y676C, and G680R substitutions were found in 2 or more patients each, representing recurrent mechanisms of PDGFRA GIST drug resistance. Notably, most PDGFRA-mutant GISTs refractory to avapritinib remain dependent on the PDGFRA oncogenic signal. Inhibitors that target PDGFRA protein stability or inhibition of PDGFRA-dependent signaling pathways may overcome avapritinib resistance.
Significance:
Here, we provide the first description of avapritinib resistance mechanisms in PDGFRA-mutant GIST.

This article is highlighted in the In This Issue feature, p. 1
Data from SWI/SNF Complex Mutations Promote Thyroid Tumor Progression and Insensitivity to Redifferentiation Therapies
Authors: Saqcena Mahesh , Leandro-Garcia Luis Javier , Maag Jesper L.V. , Tchekmedyian Vatche , Krishnamoorthy Gnana P. , Tamarapu Prasanna P. , Tiedje Vera , Reuter Vincent , Knauf Jeffrey A. , de Stanchina Elisa , Xu Bin , Liao Xiao-Hui , Refetoff Samuel , Ghossein Ronald , Chi Ping , Ho Alan L. , Koche Richard P. , Fagin James A.
Published: March 2024

Abstract
Mutations of subunits of the SWI/SNF chromatin remodeling complexes occur commonly in cancers of different lineages, including advanced thyroid cancers. Here we show that thyroid-specific loss of Arid1a, Arid2, or Smarcb1 in mouse BRAFV600E-mutant tumors promotes disease progression and decreased survival, associated with lesion-specific effects on chromatin accessibility and differentiation. As compared with normal thyrocytes, BRAFV600E-mutant mouse papillary thyroid cancers have decreased lineage transcription factor expression and accessibility to their target DNA binding sites, leading to impairment of thyroid-differentiated gene expression and radioiodine incorporation, which is rescued by MAPK inhibition. Loss of individual SWI/SNF subunits in BRAF tumors leads to a repressive chromatin state that cannot be reversed by MAPK pathway blockade, rendering them insensitive to its redifferentiation effects. Our results show that SWI/SNF complexes are central to the maintenance of differentiated function in thyroid cancers, and their loss confers radioiodine refractoriness and resistance to MAPK inhibitor–based redifferentiation therapies.
Significance:
Reprogramming cancer differentiation confers therapeutic benefit in various disease contexts. Oncogenic BRAF silences genes required for radioiodine responsiveness in thyroid cancer. Mutations in SWI/SNF genes result in loss of chromatin accessibility at thyroid lineage specification genes in BRAF-mutant thyroid tumors, rendering them insensitive to the redifferentiation effects of MAPK blockade.

This article is highlighted in the In This Issue feature, p. 995
Data from Six-Month Efficacy and Toxicity Profile of BNT162b2 Vaccine in Cancer Patients with Solid Tumors
Authors: Waldhorn Ithai , Holland Roy , Goshen-Lago Tal , Shirman Yelena , Szwarcwort-Cohen Moran , Reiner-Benaim Anat , Shachor-Meyouhas Yael , Hussein Khetam , Fahoum Liana , Peer Avivit , Almog Ronit , Shaked Yuval , Halberthal Michael , Ben-Aharon Irit
Published: March 2024

Abstract
We had previously reported short-term efficacy, immunogenicity, and safety of the BNT162b2 vaccine among cancer patients with solid tumors. We aimed to evaluate these outcomes at six months postvaccination. The study cohort comprised patients who were on treatment during vaccination and throughout six months postvaccination. Serologic tests were performed after second vaccination and six months afterward. An age-matched cohort of health care workers served as controls. Documentation of COVID-19 infection, blood tests, and imaging studies during the study period was reviewed. Participants included 154 patients and 135 controls. Six months postvaccination, 122 (79%) patients were seropositive compared with 114 (84%) controls (P = 0.32). Serology titer dramatically decreased in a similar manner in both cohorts. No COVID-19 cases were documented in controls, and one case occurred in patient cohort. All previously reported adverse effects resolved. Taken together, the pattern of immunogenicity, efficacy, and safety of BNT162b2 in patients with cancer with solid tumors at six months postvaccination resembles that of the general population.
Significance:
Evidence regarding efficacy and safety of COVID-19 vaccines in patients with cancer indicate a favorable short-term profile. Immunomodulation due to anticancer treatments may affect immunity and immunogenicity of patients with cancer to the BNT162b2 vaccine over time. Our study sheds light on these long-term outcomes and portrays a trend that resembles the general population.

This article is highlighted in the In This Issue feature, p. 2355
Data from Tilsotolimod with Ipilimumab Drives Tumor Responses in Anti–PD-1 Refractory Melanoma
Authors: Haymaker Cara , Johnson Daniel H. , Murthy Ravi , Bentebibel Salah-Eddine , Uemura Marc I. , Hudgens Courtney W. , Safa Houssein , James Marihella , Andtbacka Robert H.I. , Johnson Douglas B. , Shaheen Montaser , Davies Michael A. , Rahimian Shah , Chunduru Srinivas K. , Milton Denái R. , Tetzlaff Michael T. , Overwijk Willem W. , Hwu Patrick , Gabrail Nashat , Agrawal Sudhir , Doolittle Gary , Puzanov Igor , Markowitz Joseph , Bernatchez Chantale , Diab Adi
Published: March 2024

Abstract
Many patients with advanced melanoma are resistant to immune checkpoint inhibition. In the ILLUMINATE-204 phase I/II trial, we assessed intratumoral tilsotolimod, an investigational Toll-like receptor 9 agonist, with systemic ipilimumab in patients with anti–PD-1– resistant advanced melanoma. In all patients, 48.4% experienced grade 3/4 treatment-emergent adverse events. The overall response rate at the recommended phase II dose of 8 mg was 22.4%, and an additional 49% of patients had stable disease. Responses in noninjected lesions and in patients expected to be resistant to ipilimumab monotherapy were observed. Rapid induction of a local IFNα gene signature, dendritic cell maturation and enhanced markers of antigen presentation, and T-cell clonal expansion correlated with clinical response. A phase III clinical trial with this combination (NCT03445533) is ongoing.
Significance:
Despite recent developments in advanced melanoma therapies, most patients do not experience durable responses. Intratumoral tilsotolimod injection elicits a rapid, local type 1 IFN response and, in combination with ipilimumab, activates T cells to promote clinical activity, including in distant lesions and patients not expected to respond to ipilimumab alone.

This article is highlighted in the In This Issue feature, p. 1861
Data from Selective Modulation of a Pan-Essential Protein as a Therapeutic Strategy in Cancer
Authors: Malone Clare F. , Dharia Neekesh V. , Kugener Guillaume , Forman Alexandra B. , Rothberg Michael V. , Abdusamad Mai , Gonzalez Alfredo , Kuljanin Miljan , Robichaud Amanda L. , Conway Amy Saur , Dempster Joshua M. , Paolella Brenton R. , Dumont Nancy , Hovestadt Volker , Mancias Joseph D. , Younger Scott T. , Root David E. , Golub Todd R. , Vazquez Francisca , Stegmaier Kimberly
Published: March 2024

Abstract
Cancer dependency maps, which use CRISPR/Cas9 depletion screens to profile the landscape of genetic dependencies in hundreds of cancer cell lines, have identified context-specific dependencies that could be therapeutically exploited. An ideal therapy is both lethal and precise, but these depletion screens cannot readily distinguish between gene effects that are cytostatic or cytotoxic. Here, we use a diverse panel of functional genomic screening assays to identify NXT1 as a selective and rapidly lethal in vivo relevant genetic dependency in MYCN-amplified neuroblastoma. NXT1 heterodimerizes with NXF1, and together they form the principal mRNA nuclear export machinery. We describe a previously unrecognized mechanism of synthetic lethality between NXT1 and its paralog NXT2: their common essential binding partner NXF1 is lost only in the absence of both. We propose a potential therapeutic strategy for tumor-selective elimination of a protein that, if targeted directly, is expected to cause widespread toxicity.
Significance:
We provide a framework for identifying new therapeutic targets from functional genomic screens. We nominate NXT1 as a selective lethal target in neuroblastoma and propose a therapeutic approach where the essential protein NXF1 can be selectively eliminated in tumor cells by exploiting the NXT1–NXT2 paralog relationship.

See related commentary by Wang and Abdel-Wahab, p. 2129.

This article is highlighted in the In This Issue feature, p. 2113
Data from ZFTA–RELA Dictates Oncogenic Transcriptional Programs to Drive Aggressive Supratentorial Ependymoma
Authors: Arabzade Amir , Zhao Yanhua , Varadharajan Srinidhi , Chen Hsiao-Chi , Jessa Selin , Rivas Bryan , Stuckert Austin J. , Solis Minerva , Kardian Alisha , Tlais Dana , Golbourn Brian J. , Stanton Ann-Catherine J. , Chan Yuen San , Olson Calla , Karlin Kristen L. , Kong Kathleen , Kupp Robert , Hu Baoli , Injac Sarah G. , Ngo Madeline , Wang Peter R. , De León Luz A. , Sahm Felix , Kawauchi Daisuke , Pfister Stefan M. , Lin Charles Y. , Hodges H. Courtney , Singh Irtisha , Westbrook Thomas F. , Chintagumpala Murali M. , Blaney Susan M. , Parsons Donald W. , Pajtler Kristian W. , Agnihotri Sameer , Gilbertson Richard J. , Yi Joanna , Jabado Nada , Kleinman Claudia L. , Bertrand Kelsey C. , Deneen Benjamin , Mack Stephen C.
Published: March 2024

Abstract
More than 60% of supratentorial ependymomas harbor a ZFTA–RELA (ZRfus) gene fusion (formerly C11orf95–RELA). To study the biology of ZRfus, we developed an autochthonous mouse tumor model using in utero electroporation (IUE) of the embryonic mouse brain. Integrative epigenomic and transcriptomic mapping was performed on IUE-driven ZRfus tumors by CUT&RUN, chromatin immunoprecipitation sequencing, assay for transposase-accessible chromatin sequencing, and RNA sequencing and compared with human ZRfus-driven ependymoma. In addition to direct canonical NFκB pathway activation, ZRfus dictates a neoplastic transcriptional program and binds to thousands of unique sites across the genome that are enriched with PLAGL family transcription factor (TF) motifs. ZRfus activates gene expression programs through recruitment of transcriptional coactivators (Brd4, Ep300, Cbp, Pol2) that are amenable to pharmacologic inhibition. Downstream ZRfus target genes converge on developmental programs marked by PLAGL TF proteins, and activate neoplastic programs enriched in Mapk, focal adhesion, and gene imprinting networks.
Significance:
Ependymomas are aggressive brain tumors. Although drivers of supratentorial ependymoma (ZFTA- and YAP1-associated gene fusions) have been discovered, their functions remain unclear. Our study investigates the biology of ZFTA–RELA-driven ependymoma, specifically mechanisms of transcriptional deregulation and direct downstream gene networks that may be leveraged for potential therapeutic testing.

This article is highlighted in the In This Issue feature, p. 2113
Data from Werner Helicase Is a Synthetic-Lethal Vulnerability in Mismatch Repair–Deficient Colorectal Cancer Refractory to Targeted Therapies, Chemotherapy, and Immunotherapy
Authors: Picco Gabriele , Cattaneo Chiara M. , van Vliet Esmée J. , Crisafulli Giovanni , Rospo Giuseppe , Consonni Sarah , Vieira Sara F. , Rodríguez Iñigo Sánchez , Cancelliere Carlotta , Banerjee Ruby , Schipper Luuk J. , Oddo Daniele , Dijkstra Krijn K. , Cinatl Jindrich , Michaelis Martin , Yang Fengtang , Di Nicolantonio Federica , Sartore-Bianchi Andrea , Siena Salvatore , Arena Sabrina , Voest Emile E. , Bardelli Alberto , Garnett Mathew J.
Published: March 2024

Abstract
Targeted therapies, chemotherapy, and immunotherapy are used to treat patients with mismatch repair–deficient (dMMR)/microsatellite instability-high (MSI-H) colorectal cancer. The clinical effectiveness of targeted therapy and chemotherapy is limited by resistance and drug toxicities, and about half of patients receiving immunotherapy have disease that is refractory to immune checkpoint inhibitors. Loss of Werner syndrome ATP-dependent helicase (WRN) is a synthetic lethality in dMMR/MSI-H cells. To inform the development of WRN as a therapeutic target, we performed WRN knockout or knockdown in 60 heterogeneous dMMR colorectal cancer preclinical models, demonstrating that WRN dependency is an almost universal feature and a robust marker for patient selection. Furthermore, models of resistance to clinically relevant targeted therapy, chemotherapy, and immunotherapy retain WRN dependency. These data show the potential of therapeutically targeting WRN in patients with dMMR/MSI-H colorectal cancer and support WRN as a therapeutic option for patients with dMMR/MSI-H cancers refractory to current treatment strategies.
Significance:
We found that a large, diverse set of dMMR/MSI-H colorectal cancer preclinical models, including models of treatment-refractory disease, are WRN-dependent. Our results support WRN as a promising synthetic-lethal target in dMMR/MSI-H colorectal cancer tumors as a monotherapy or in combination with targeted agents, chemotherapy, or immunotherapy.

This article is highlighted in the In This Issue feature, p. 1861
Data from Peripheral Blood TCR Repertoire Profiling May Facilitate Patient Stratification for Immunotherapy against Melanoma
Authors: Hogan Sabrina A. , Courtier Anaïs , Cheng Phil F. , Jaberg-Bentele Nicoletta F. , Goldinger Simone M. , Manuel Manuarii , Perez Solène , Plantier Nadia , Mouret Jean-François , Nguyen-Kim Thi Dan Linh , Raaijmakers Marieke I.G. , Kvistborg Pia , Pasqual Nicolas , Haanen John B.A.G. , Dummer Reinhard , Levesque Mitchell P.
Published: March 2024

Abstract
Many metastatic melanoma patients experience durable responses to anti-PD1 and/or anti-CTLA4; however, a significant proportion (over 50%) do not benefit from the therapies. In this study, we sought to assess pretreatment liquid biopsies for biomarkers that may correlate with response to checkpoint blockade. We measured the combinatorial diversity evenness of the T-cell receptor (TCR) repertoire (the DE50, with low values corresponding to more clonality and lack of TCR diversity) in pretreatment peripheral blood mononuclear cells from melanoma patients treated with anti-CTLA4 (n = 42) or anti-PD1 (n = 38) using a multi-N-plex PCR assay on genomic DNA (gDNA). A receiver operating characteristic curve determined the optimal threshold for a dichotomized analysis according to objective responses as defined by RECIST1.1. Correlations between treatment outcome, clinical variables, and DE50 were assessed in multivariate regression models and confirmed with Fisher exact tests. In samples obtained prior to treatment initiation, we showed that low DE50 values were predictive of a longer progression-free survival and good responses to PD-1 blockade, but, on the other hand, predicted a poor response to CTLA4 inhibition. Multivariate logistic regression models identified DE50 as the only independent predictive factor for response to anti-CTLA4 therapy (P = 0.03) and anti-PD1 therapy (P = 0.001). Fisher exact tests confirmed the association of low DE50 with response in the anti-CTLA4 (P = 0.041) and the anti-PD1 cohort (P = 0.0016). Thus, the evaluation of basal TCR repertoire diversity in peripheral blood, using a PCR-based method, could help predict responses to anti-PD1 and anti-CTLA4 therapies.
Data from Immunosurveillance and Immunoediting of Breast Cancer via Class I MHC Receptors
Authors: Tu Megan M. , Rahim Mir Munir A. , Sayed Céline , Mahmoud Ahmad Bakur , Makrigiannis Andrew P.
Published: March 2024

Abstract
Ly49 receptors, which recognize “self” class I major histocompatibility complex (MHC-I) molecules, enable natural killer (NK) cells to detect loss of MHC-I expression on transformed and virally infected cells. The impact of NK cell–mediated MHC-I surveillance on immunoediting of breast cancer is still not fully understood. This work assesses the impact of Ly49 receptors on tumor development in terms of cancer control and in driving immune-evading cancer mutations. Genetically modified Ly49-deficient mice and those lacking NK cells through antibody depletion were less able to control E0771-derived mammary tumors in an MHC-I–dependent fashion. Similarly, Ly49-deficient MMTV-PyVT–transgenic mice developed spontaneous mammary tumors faster than Ly49-sufficient MMTV-PyVT mice. Fewer CD69+ and granzyme B+ NK cells were detected among the tumor-infiltrating lymphocytes in Ly49-deficient than in Ly49-sufficient MMTV-PyVT mice. Furthermore, tumors from Ly49-deficient mice displayed reduced MHC-I expression, suggesting that tumors growing in these mice lacked an Ly49-derived pressure to maintain MHC-I expression. These same MHC-I-low tumors from Ly49-deficient mice were unable to flourish when transferred to Ly49-sufficient hosts, confirming that this tumor mutation was in response to an Ly49-deficient environment. This work demonstrates a role for Ly49 receptors in the control of mammary cancer, and provides evidence to support a model of tumor immunoediting, in which selective pressures from the immune system drive immune-evasive cancer mutations. Cancer Immunol Res; 5(11); 1016–28. ©2017 AACR.