Cancer Biology

MDM2 stabilization of Notch intracellular domain upon DNA damage plays a major role in non-small cell lung carcinoma response to platinum chemotherapy

1. Sara Bernardo
2. Quentin-Dominique Thomas
3. Maicol Mancini
4. Alba Santos
5. Sylvia Fenosoa Rasamizafy
6. Amina-Milissa Maacha
7. Anais Giry
8. Emilie Bousquet-Mur
9. Laura Papon
10. Marion Goussard
11. Christophe Fremin
12. Andrea Pasquier
13. María Rodríguez
14. Camille Travert
15. Jean-Louis Pujol
16. Laetitia K Linares
17. Lisa Heron-Milhavet
18. Alexandre Djiane
19. Irene Ferrer
20. Luis Paz-Ares
21. Xavier Quantin
22. Luis M Montuenga
23. Hélène Tourriere
24. Antonio Maraver

Reviewed by Review Commons

Identification of nonsense-mediated decay inhibitors that alter the tumor immune landscape

1. Ashley L Cook
2. Surojit Sur
3. Laura Dobbyn
4. Evangeline Watson
5. Joshua D Cohen
6. Blair Ptak
7. Bum Seok Lee
8. Suman Paul
9. Emily Hsiue
10. Maria Popoli
11. Bert Vogelstein
12. Nickolas Papadopoulos
13. Chetan Bettegowda
14. Kathy Gabrielson
15. Shibin Zhou
16. Kenneth W Kinzler
17. Nicolas Wyhs

• Curated by eLife

  eLife assessment

  Here, the authors developed a cell-based screening assay for the identification of small molecule inhibitors of nonsense-mediated decay (NMD), and used it to validate KVS0001, a new small molecule SMG1 kinase inhibitor derived from the existing inhibitor SMG1i-11, showing it inhibits NMD in cultured cells leading to expression of neoantigens from NMD-targeted genes and slows tumor growth of cancer cell lines possessing a significant number of out-of-frame indel mutations. The conclusions are supported by convincing evidence, and the significance of this work consists in the development of a new and very promising NMD inhibitor drug that acts as an inhibitor of the SMG1 NMD kinase and is effective in animal tumor studies. This is an important advance for the field, as previous NMD inhibitors were not specific, lacked efficacy, or were very toxic and hence not suitable for animal applications.

Reviewed by eLife

Resistance to PSEN1-selective γ-secretase inhibitors in T-cell acute lymphoblastic leukemia

1. Charlien Vandersmissen
2. Sofie Demeyer
3. Kris Jacobs
4. Lien Boogaerts
5. Sara Gutiérrez Fernández
6. Heidi Segers
7. Lucía Chávez-Gutiérrez
8. Jan Cools

Reviewed by Review Commons

The DBD-α4 helix of EWSR1::FLI1 is required for GGAA microsatellite binding that underlies genome regulation in Ewing sarcoma

1. Ariunaa Bayanjargal
2. Cenny Taslim
3. Iftekhar A Showpnil
4. Julia Selich-Anderson
5. Jesse C Crow
6. Stephen L Lessnick
7. Emily R Theisen

• Curated by eLife

  eLife assessment

  This paper investigates how the EWS::FLI1 fusion protein organizes chromatin topology and regulates gene expression in an aggressive pediatric bone cancer known as Ewing sarcoma. The authors used the most recent genomics methodologies to provide solid-based evidence for the role of a short alpha helix in the DNA binding domain of FLI1 in modulating binding to GGAA microsatellites and promoting enhancer activity. The study provides valuable insight into the underlying oncogenic mechanisms in Ewing sarcoma, despite the inherent limitations of the some of the techniques used.

Reviewed by eLife

Aging represses lung tumorigenesis and alters tumor suppression

1. Emily G. Shuldiner
2. Saswati Karmakar
3. Min K. Tsai
4. Jess D. Hebert
5. Yuning J. Tang
6. Laura Andrejka
7. Minwei Wang
8. Colin R. Detrick
9. Hongchen Cai
10. Rui Tang
11. Dmitri A. Petrov
12. Monte M. Winslow

Reviewed by PREreview

Patient-derived xenografts and single-cell sequencing identifies three subtypes of tumor-reactive lymphocytes in uveal melanoma metastases

1. Joakim W Karlsson
2. Vasu R Sah
3. Roger Olofsson Bagge
4. Irina Kuznetsova
5. Munir Iqba
6. Samuel Alsen
7. Sofia Stenqvist
8. Alka Saxena
9. Lars Ny
10. Lisa M Nilsson
11. Jonas A Nilsson

• Curated by eLife

  eLife assessment

  This study presents valuable findings on tumor-reactive T cells in liver metastases of uveal melanoma (UM). The authors conducted single-cell RNA sequencing to identify potential tumor-reactive T cells and used PDX models for functional analysis. The evidence supporting their claims is solid. The work will be of interest to scientists working in the field of uveal melanoma.

Reviewed by eLife

NPRL2 gene therapy induces effective antitumor immunity in KRAS/STK11 mutant anti-PD1 resistant metastatic non-small cell lung cancer (NSCLC) in a humanized mouse model

1. Ismail M Meraz
2. Mourad Majidi
3. Renduo Song
4. Feng Meng
5. Lihui Gao
6. Qi Wang
7. Jing Wang
8. Elizabeth J Shpall
9. Jack A Roth

• Curated by eLife

  eLife assessment

  This study provides a novel and promising NPRL2 gene therapy for enhanced immunotherapy response in a KRAS/STK11 mutant anti-PD1 resistant metastatic NSCLC humanized mouse model. Overall, the authors presented a large amount of convincing in vivo data to demonstrate that NPRL2 gene therapy induces antitumor activity through DC-mediated antigen presentation and cytotoxic immune cell activation. This work will be of interest and useful to medical biologists and oncologists in the research field of KRAS-mutant NSCLC.

Reviewed by eLife

PITAR, a DNA damage-inducible cancer/testis long noncoding RNA, inactivates p53 by binding and stabilizing TRIM28 mRNA

1. Samarjit Jana
2. Mainak Mondal
3. Sagar Mahale
4. Bhavana Gupta
5. Kaval Reddy Prasasvi
6. Lekha Kandasami
7. Neha Jha
8. Abhishek Chowdhury
9. Vani Santosh
10. Chandrasekhar Kanduri
11. Kumaravel Somasundaram

• Curated by eLife

  eLife assessment

  This important study reports, with convincing evidence, that a long non-coding RNA disrupts the activity of the tumor suppressor p53 to contribute to the growth and therapeutic response of glioblastoma. The work will be relevant to scientists working on non-coding RNAs and brain tumors.

Reviewed by eLife

Dual targeting of histone deacetylases and MYC as potential treatment strategy for H3-K27M pediatric gliomas

1. Danielle Algranati
2. Roni Oren
3. Bareket Dassa
4. Liat Fellus-Alyagor
5. Alexander Plotnikov
6. Haim Barr
7. Alon Harmelin
8. Nir London
9. Guy Ron
10. Noa Furth
11. Efrat Shema

• Curated by eLife

  eLife assessment

  This work contributes to the study of H3-K27M mutated pediatric gliomas. It convincingly demonstrates that the concomitant targeting of histone deacetylases (HDACs) and the transcription factor MYC results in a notable reduction in cell viability and tumor growth. This reduction is linked to the suppression of critical oncogenic pathways, particularly mTOR signaling, emphasizing the role of these pathways in the disease's pathogenesis. The current version of the manuscript is important because it unveils a vulnerability from dual targeting HDACs and MYC in the context of pediatric gliomas. This work will be of interest to cancer epigenetics and therapeutics research, with a focus on the neuro-oncology field.

Reviewed by eLife

Timing of treatment shapes the path to androgen receptor signaling inhibitor resistance in prostate cancer

1. Eugine Lee
2. Zeda Zhang
3. Chi-Chao Chen
4. Danielle Choi
5. Aura C. Agudelo Rivera
6. Eliot Linton
7. Yu-jui Ho
8. Jillian Love
9. Justin LaClair
10. John Wongvipat
11. Charles L. Sawyers

• Curated by eLife

  eLife assessment

  This important study provides new insight into the dynamics that underlie the development of therapy resistance in prostate cancer by revealing that divergent tumor evolutionary paths occur in response to different treatment timing and that these converge on common resistance mechanisms. The use of barcoded lineage tracing and characterization of isolated tumor clonal populations provides compelling evidence supporting the importance of clonal dynamics in a tumor ecosystem for treatment resistance. Several open questions remain, however, raising the possibility of alternative interpretations of the data set in its current form. Overall, the findings deepen our understanding of prostate cancer evolution and hold promising implications for how drug resistance can be addressed or prevented.

Reviewed by eLife