The spindle assembly checkpoint is a therapeutic vulnerability of CDK4/6 inhibitor–resistant ER + breast cancer with mitotic aberrations DOI Creative Commons
Isabel Soria‐Bretones, Kelsie L. Thu, Jennifer Silvester

et al.

Science Advances, Journal Year: 2022, Volume and Issue: 8(36)

Published: Sept. 7, 2022

Inhibitors of cyclin-dependent kinases 4 and 6 (CDK4/6i) are standard first-line treatments for metastatic ER + breast cancer. However, acquired resistance to CDK4/6i invariably develops, the molecular phenotypes exploitable vulnerabilities associated with not yet fully characterized. We developed a panel CDK4/6i-resistant cancer cell lines patient-derived organoids demonstrate that subset resistant models accumulates mitotic segregation errors micronuclei, displaying increased sensitivity inhibitors checkpoint regulators TTK Aurora kinase A/B. RB1 loss, well-recognized mechanism resistance, causes such defects confers enhanced inhibition. In these models, inhibition CFI-402257 induces premature chromosome segregation, leading excessive errors, DNA damage, death. These findings nominate inhibitor as therapeutic strategy defined patients who develop CDK4/6i.

Language: Английский

Cytidine deaminases APOBEC3C and APOBEC3D promote DNA replication stress resistance in pancreatic cancer cells DOI
Tajinder Ubhi, Olga Zaslaver, Andrew T. Quaile

et al.

Nature Cancer, Journal Year: 2024, Volume and Issue: 5(6), P. 895 - 915

Published: March 6, 2024

Language: Английский

Citations

8
Single-cell Transcriptomics Reveals the Aggressive Landscape of High-Grade Serous Carcinoma and Therapeutic Targets in Tumor Microenvironment DOI Creative Commons
Junfen Xu,

Weiguo Lü,

Xinyi Wei

et al.

Cancer Letters, Journal Year: 2024, Volume and Issue: 593, P. 216928 - 216928

Published: May 5, 2024

High-grade serous carcinoma (HGSC) is characterized by early abdominal metastasis, leading to a dismal prognosis. In this study, we conducted single-cell RNA sequencing on 109,573 cells from 34 tumor samples of 18 HGSC patients, including both primary tumors and their metastatic sites. Our analysis revealed distinct S100A9

Language: Английский

Citations

8
Transcriptome-scale RNA-targeting CRISPR screens reveal essential lncRNAs in human cells DOI
Wen-Wei Liang, Simon Müller, Sydney K. Hart

et al.

Cell, Journal Year: 2024, Volume and Issue: unknown

Published: Nov. 1, 2024

Language: Английский

Citations

8
Discovery of an Orally Bioavailable and Selective PKMYT1 Inhibitor, RP-6306 DOI
Janek Szychowski, Robert Papp, Evelyne Dietrich

et al.

Journal of Medicinal Chemistry, Journal Year: 2022, Volume and Issue: 65(15), P. 10251 - 10284

Published: July 26, 2022

PKMYT1 is a regulator of CDK1 phosphorylation and compelling therapeutic target for the treatment certain types DNA damage response cancers due to its established synthetic lethal relationship with CCNE1 amplification. To date, no selective inhibitors have been reported this kinase that would allow investigation pharmacological role PKMYT1. address need compound 1 was identified as weak inhibitor. Introduction dimethylphenol increased potency on These analogs were found exist atropisomers could be separated profiled single enantiomers. Structure-based drug design enabled optimization cell-based potency. Parallel ADME properties led identification potent RP-6306 inhibits CCNE1-amplified tumor cell growth in several preclinical xenograft models. The first-in-class clinical candidate currently being evaluated Phase trials various solid tumors.

Language: Английский

Citations

32
The spindle assembly checkpoint is a therapeutic vulnerability of CDK4/6 inhibitor–resistant ER + breast cancer with mitotic aberrations DOI Creative Commons
Isabel Soria‐Bretones, Kelsie L. Thu, Jennifer Silvester

et al.

Science Advances, Journal Year: 2022, Volume and Issue: 8(36)

Published: Sept. 7, 2022

Inhibitors of cyclin-dependent kinases 4 and 6 (CDK4/6i) are standard first-line treatments for metastatic ER + breast cancer. However, acquired resistance to CDK4/6i invariably develops, the molecular phenotypes exploitable vulnerabilities associated with not yet fully characterized. We developed a panel CDK4/6i-resistant cancer cell lines patient-derived organoids demonstrate that subset resistant models accumulates mitotic segregation errors micronuclei, displaying increased sensitivity inhibitors checkpoint regulators TTK Aurora kinase A/B. RB1 loss, well-recognized mechanism resistance, causes such defects confers enhanced inhibition. In these models, inhibition CFI-402257 induces premature chromosome segregation, leading excessive errors, DNA damage, death. These findings nominate inhibitor as therapeutic strategy defined patients who develop CDK4/6i.

Language: Английский

Citations

30