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Peer-reviewedCC BYScience Advances

Sensitizing tumor response to topoisomerase I antibody-drug conjugate by selective CDK7 inhibition

  • Hyerim Jung1
  • Yoonji Lee2
  • Donghoon Yu2
  • Yeejin Jeon2
  • Hwankyu Kang2
  • Dahun Um1
  • Mooyoung Seo2
  • Dongsik Park2
  • Jeongjun Kim2
  • Seung-Joo Lee2
  • Jaeseung Kim2
  • Lauren Escobedo3
4 more authors
  • Yilun Sun3
  • Anish Thomas4
  • Kiyean Nam2
  • Tae-Kyung Kim1
4 affiliations
  1. 1Department of Life Sciences, Pohang University of Science and Technology, Pohang, Gyeongbuk 37673, Korea.
  2. 2Qurient Co. Ltd., C801, 242 Pangyo-ro, Bundang-gu, Seongnam-si, Gyeonggi-do 13487, Korea.
  3. 3University of Maryland Marlene & Stewart Greenebaum Comprehensive Cancer Center, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
  4. 4Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892, USA.
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Abstract

This study investigates the transcriptional impact of Q901, a highly selective CDK7 inhibitor in clinical development. Q901 primarily disrupted MYC and E2F-dependent transcription program, downregulating cell cycle control and DNA damage repair pathways. CDK7 binding at the promoter-proximal regions was dramatically stabilized by Q901, leading to reduced occupancy of MYC, E2F, and RNA Polymerase II (RNAPII). These findings offered a novel therapeutic strategy to enhance cancer susceptibility to TOP1-DNA protein crosslinks (TOP1-DPCs) induced by TOP1 inhibitors. Resistance to TOP1 inhibitors arises through activation of DNA repair pathway when elongating RNAPII encounters TOP1-DPCs. By suppressing RNAPII transition from initiation to elongation and DNA repair pathways, Q901 stabilizes TOP1-DPCs and sensitizes tumor to TOP1 inhibitors. Preclinical studies demonstrated enhanced tumor suppression when combining Q901 with TOP1 inhibitor-based antibody-drug conjugates (TOP1i-ADCs), highlighting its potential as a therapeutic option for cancers resistant to TOP1i-ADC therapy.

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Cite

BibTeXRIS
BibTeX
@article{jung2026sensitizing,
  title = {{Sensitizing tumor response to topoisomerase I antibody-drug conjugate by selective CDK7 inhibition}},
  author = {Hyerim Jung and Yoonji Lee and Donghoon Yu and Yeejin Jeon and Hwankyu Kang and Dahun Um and Mooyoung Seo and Dongsik Park and Jeongjun Kim and Seung-Joo Lee and Jaeseung Kim and Lauren Escobedo and Yilun Sun and Anish Thomas and Kiyean Nam and Tae-Kyung Kim},
  journal = {Science Advances},
  year = {2026},
  month = oct,
  doi = {10.1126/sciadv.aeb4023},
  url = {https://www.science.org/doi/10.1126/sciadv.aeb4023},
  note = {CC BY},
}
RIS
TY  - JOUR
TI  - Sensitizing tumor response to topoisomerase I antibody-drug conjugate by selective CDK7 inhibition
AU  - Hyerim Jung
AU  - Yoonji Lee
AU  - Donghoon Yu
AU  - Yeejin Jeon
AU  - Hwankyu Kang
AU  - Dahun Um
AU  - Mooyoung Seo
AU  - Dongsik Park
AU  - Jeongjun Kim
AU  - Seung-Joo Lee
AU  - Jaeseung Kim
AU  - Lauren Escobedo
AU  - Yilun Sun
AU  - Anish Thomas
AU  - Kiyean Nam
AU  - Tae-Kyung Kim
PY  - 2026
DA  - 2026/10/02
JO  - Science Advances
DO  - 10.1126/sciadv.aeb4023
UR  - https://www.science.org/doi/10.1126/sciadv.aeb4023
AB  - This study investigates the transcriptional impact of Q901, a highly selective CDK7 inhibitor in clinical development. Q901 primarily disrupted MYC and E2F-dependent transcription program, downregulating cell cycle control and DNA damage repair pathways. CDK7 binding at the promoter-proximal regions was dramatically stabilized by Q901, leading to reduced occupancy of MYC, E2F, and RNA Polymerase II (RNAPII). These findings offered a novel therapeutic strategy to enhance cancer susceptibility to TOP1-DNA protein crosslinks (TOP1-DPCs) induced by TOP1 inhibitors. Resistance to TOP1 inhibitors arises through activation of DNA repair pathway when elongating RNAPII encounters TOP1-DPCs. By suppressing RNAPII transition from initiation to elongation and DNA repair pathways, Q901 stabilizes TOP1-DPCs and sensitizes tumor to TOP1 inhibitors. Preclinical studies demonstrated enhanced tumor suppression when combining Q901 with TOP1 inhibitor-based antibody-drug conjugates (TOP1i-ADCs), highlighting its potential as a therapeutic option for cancers resistant to TOP1i-ADC therapy.
SN  - 2375-2548
ER  -