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Your search keyword '"Sebastijan Hobor"' showing total 3 results
Start Over Author "Sebastijan Hobor" Journal nature communications
3 results on '"Sebastijan Hobor"'

1. Mixed responses to targeted therapy driven by chromosomal instability through p53 dysfunction and genome doubling

Author

Sebastijan Hobor, Maise Al Bakir, Crispin T. Hiley, Marcin Skrzypski, Alexander M. Frankell, Bjorn Bakker, Thomas B. K. Watkins, Aleksandra Markovets, Jonathan R. Dry, Andrew P. Brown, Jasper van der Aart, Hilda van den Bos, Diana Spierings, Dahmane Oukrif, Marco Novelli, Turja Chakrabarti, Adam H. Rabinowitz, Laila Ait Hassou, Saskia Litière, D. Lucas Kerr, Lisa Tan, Gavin Kelly, David A. Moore, Matthew J. Renshaw, Subramanian Venkatesan, William Hill, Ariana Huebner, Carlos Martínez-Ruiz, James R. M. Black, Wei Wu, Mihaela Angelova, Nicholas McGranahan, Julian Downward, Juliann Chmielecki, Carl Barrett, Kevin Litchfield, Su Kit Chew, Collin M. Blakely, Elza C. de Bruin, Floris Foijer, Karen H. Vousden, Trever G. Bivona, TRACERx consortium, Robert E. Hynds, Nnennaya Kanu, Simone Zaccaria, Eva Grönroos, and Charles Swanton

Subjects
Science
Abstract

Abstract The phenomenon of mixed/heterogenous treatment responses to cancer therapies within an individual patient presents a challenging clinical scenario. Furthermore, the molecular basis of mixed intra-patient tumor responses remains unclear. Here, we show that patients with metastatic lung adenocarcinoma harbouring co-mutations of EGFR and TP53, are more likely to have mixed intra-patient tumor responses to EGFR tyrosine kinase inhibition (TKI), compared to those with an EGFR mutation alone. The combined presence of whole genome doubling (WGD) and TP53 co-mutations leads to increased genome instability and genomic copy number aberrations in genes implicated in EGFR TKI resistance. Using mouse models and an in vitro isogenic p53-mutant model system, we provide evidence that WGD provides diverse routes to drug resistance by increasing the probability of acquiring copy-number gains or losses relative to non-WGD cells. These data provide a molecular basis for mixed tumor responses to targeted therapy, within an individual patient, with implications for therapeutic strategies.

Published
2024
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2. Selective inhibition of cancer cell self-renewal through a Quisinostat-histone H1.0 axis

Author

Cristina Morales Torres, Mary Y. Wu, Sebastijan Hobor, Elanor N. Wainwright, Matthew J. Martin, Harshil Patel, William Grey, Eva Grönroos, Steven Howell, Joana Carvalho, Ambrosius P. Snijders, Michael Bustin, Dominique Bonnet, Paul D. Smith, Charles Swanton, Michael Howell, and Paola Scaffidi

Subjects
Science
Abstract

Targeting self-renewing cancer cells without deleterious side effects in normal tissues has proven challenging. Here, the authors show that the well-tolerated HDAC inhibitor Quisinostat safely inhibits tumor maintenance and disease relapse by restoring high levels of histone H1.0.

Published
2020
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3. Selective inhibition of cancer cell self-renewal through a Quisinostat-histone H1.0 axis

Author

Michael Bustin, Michael Howell, Harshil Patel, Joana Carvalho, Elanor N. Wainwright, Mary Y. Wu, Steven Howell, Paola Scaffidi, Ambrosius P. Snijders, Paul D. Smith, Dominique Bonnet, Cristina Morales Torres, William Grey, Eva Grönroos, Sebastijan Hobor, Matthew J. Martin, and Charles Swanton

Subjects
0301 basic medicine, Tumour heterogeneity, Cancer therapy, Cell Survival, medicine.medical_treatment, Science, General Physics and Astronomy, Hydroxamic Acids, General Biochemistry, Genetics and Molecular Biology, Article, Targeted therapy, Histones, 03 medical and health sciences, Mice, 0302 clinical medicine, Histone H1, Recurrence, Cell Line, Tumor, Neoplasms, medicine, Animals, Humans, Epigenetics, Cell Self Renewal, Lung cancer, lcsh:Science, Cell Proliferation, Multidisciplinary, business.industry, Cancer, Cell Differentiation, General Chemistry, medicine.disease, Hematopoietic Stem Cells, 3. Good health, Gene Expression Regulation, Neoplastic, Histone Deacetylase Inhibitors, 030104 developmental biology, 030220 oncology & carcinogenesis, Cancer cell, Cancer research, lcsh:Q, Stem cell, business
Abstract

Continuous cancer growth is driven by subsets of self-renewing malignant cells. Targeting of uncontrolled self-renewal through inhibition of stem cell-related signaling pathways has proven challenging. Here, we show that cancer cells can be selectively deprived of self-renewal ability by interfering with their epigenetic state. Re-expression of histone H1.0, a tumor-suppressive factor that inhibits cancer cell self-renewal in many cancer types, can be broadly induced by the clinically well-tolerated compound Quisinostat. Through H1.0, Quisinostat inhibits cancer cell self-renewal and halts tumor maintenance without affecting normal stem cell function. Quisinostat also hinders expansion of cells surviving targeted therapy, independently of the cancer types and the resistance mechanism, and inhibits disease relapse in mouse models of lung cancer. Our results identify H1.0 as a major mediator of Quisinostat’s antitumor effect and suggest that sequential administration of targeted therapy and Quisinostat may be a broadly applicable strategy to induce a prolonged response in patients., Targeting self-renewing cancer cells without deleterious side effects in normal tissues has proven challenging. Here, the authors show that the well-tolerated HDAC inhibitor Quisinostat safely inhibits tumor maintenance and disease relapse by restoring high levels of histone H1.0.

Published
2020

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