SPHINX31 acts as a SRPK1 inhibitor targeting the ATR / DNA ‐ PKcs / CHK1 replicative checkpoint to inhibit cell growth in non‐small cell lung cancer
Splicing targeting drugs have emerged as promising anticancer drugs. However, their mechanisms of action remain largely unknown, notably in Non-Small Cell Lung Carcinoma (NSCLC). In this study, we demonstrated that SPHINX31, which targets SRPK1, inhibits the ATR/CHK1 signaling pathway, a cornerstone of the replicative stress response, leading to decreased cell proliferation, increased DNA damage and apoptosis, notably in NSCLC cells resistant to platinum salts. Mechanistically, we found that SRPK1 is recruited at stalled replication forks upon replicative stress, co-immunoprecipitates with the ATR/ATRIP/TOPBP1 complex, directly interacts with TOPBP1 BRCT4/5 and BRCT7/8 domains, and contributes to the accumulation of TOPBP1 nuclear foci. We further showed that SRPK1 controls the splicing of genes previously related to ATR signaling, notably WIZ. All these events are prevented by SPHINX31. Lastly, we showed that the inhibitory effects of SPHINX31 on ATR are counterbalanced by the activation of DNA-PKcs. Altogether, this study uncovers SRPK1 as a new component of the ATR/DNA-PKcs/CHK1 replicative checkpoint. SRPK1 inhibitors, alone or in combination with DNA-PKcs or CHK1 inhibitors, could provide therapeutic benefit in NSCLC patients including those who relapse after platinum-based chemotherapy.
Authors
- Adiilah Mamode Cassim (ORCID: https://orcid.org/0000-0002-7950-0504)
- Aurélie Genoux (ORCID: https://orcid.org/0000-0002-1397-191X)
- Fabien Dalonneau
- C. Garrido
- Haoyang Zheng (ORCID: https://orcid.org/0000-0001-6835-8242)
- Béatrice Eymin (ORCID: https://orcid.org/0000-0002-7311-3810)
- Eleni Nikolakaki (ORCID: https://orcid.org/0000-0003-3388-3850)
- Tao Jia (ORCID: https://orcid.org/0000-0002-8358-6005)
- Sophie Zinn‐Justin (ORCID: https://orcid.org/0000-0002-7680-1088)
- Didier Auboeuf (ORCID: https://orcid.org/0000-0002-3757-0002)
- Théo Ziegelmeyer (ORCID: https://orcid.org/0000-0002-8454-3410)
- Hélène Polvèche (ORCID: https://orcid.org/0000-0002-5601-3498)
- Perla Salameh (ORCID: https://orcid.org/0000-0002-0170-841X)
- Amani Shreim
- Nadiia Zubchuk (ORCID: https://orcid.org/0009-0007-7282-2133)
- Christiane Oddou
- Simona Miron (ORCID: https://orcid.org/0000-0003-2078-9582)
- Margot Rouchette
Institutions
- Université Claude Bernard Lyon 1 (FR)
- École Normale Supérieure de Lyon (FR)
- Centre National de la Recherche Scientifique (FR)
- Inserm (FR)
- Aristotle University of Thessaloniki (GR)
- Commissariat à l'Énergie Atomique et aux Énergies Alternatives (FR)
- Université Paris-Saclay (FR)
- Centre Georges François Leclerc (FR)
- Mianyang Central Hospital (CN)
- Laboratoire de Biologie et Modélisation de la Cellule (FR)
- Institut de Biologie Intégrative de la Cellule (FR)
- Centre Hospitalier Sud Francilien (FR)
- CEA Paris-Saclay (FR)
- Université Grenoble Alpes (FR)
Publication Details
- Journal
- Molecular Oncology
- Published
- 2026-09-17
- DOI
- https://doi.org/10.1002/1878-0261.70339
- Primary Topic
- DNA Repair Mechanisms
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Fondation du Souffle
- Communauté Université Grenoble Alpes
- Society of Interventional Radiology Foundation
- Infrastructures en Biologie Santé et Agronomie
- Agence Nationale de la Recherche
- Institut National de la Santé et de la Recherche Médicale
- Ligue Contre le Cancer
- Ministère de l'Education Nationale, de l'Enseignement Superieur et de la Recherche
- Centre National de la Recherche Scientifique
- Institut National Du Cancer
- French Infrastructure for Integrated Structural Biology
- Groupement des Entreprises Françaises dans la lutte contre le Cancer