Avelumab Versus Docetaxel in Patients With Platinum-Treated Advanced NSCLC: 2-Year Follow-Up From the JAVELIN Lung 200 Phase 3 Trial

Florian Roisné-Hamelin (1) , Sabrina Pobiega (1) , Kévin Jézéquel (1) , Simona Miron (2) , Jordane Dépagne (1) , Xavier Veaute (1) , Didier Busso (1) , Marie-Hélène Le Du (2) , Isabelle Callebaut (3) , Jean-Baptiste Charbonnier (2) , Philippe Cuniasse (2) , Sophie Zinn-Justin (2) , Stéphane Marcand (1) , Keunchil Park (4) , Mustafa Özgüroğlu (5) , Johan Vansteenkiste (6) , David Spigel (7) , James C.H. Yang (8) , Hidenobu Ishii , Marina Garassino (9) , Filippo de Marinis , Aleksandra Szczesna , Andreas Polychronis , Ruchan Uslu , Maciej Krzakowski (10) , Jong-Seok Lee (11) , Luana Calabrò (12) , Osvaldo Arén Frontera , Huiling Xiong , Marcis Bajars (13) , Mary Ruisi (13) , Fabrice Barlesi (14, 15)

1 JACOB - Institut de Biologie François JACOB
2 I2BC - Institut de Biologie Intégrative de la Cellule
3 IMPMC - Institut de minéralogie, de physique des matériaux et de cosmochimie
4 Samsung Medical Center Sungkyunkwan University School of Medicine
5 Istanbul University Cerrahpasa
6 Department of Pulmonology
7 Sarah Cannon Research Institute [Nashville, Tennessee]
8 National Taiwan University Cancer Center [Taipei]
9 IRCCS Istituto Nazionale dei Tumori [Milano]
10 Institut de Recherche Pierre Fabre
11 SNUBH - Seoul National University Bundang Hospital
12 Azienda Ospedaliera Universitaria Senese
13 EMD Serono Research & Development Institute
14 IGR - Institut Gustave Roussy
15 CRCM - Centre de Recherche en Cancérologie de Marseille

Abstract Specific proteins present at telomeres ensure chromosome end stability, in large part through unknown mechanisms. In this work, we address how the Saccharomyces cerevisiae ORC-related Rif2 protein protects telomere. We show that the small N-terminal Rif2 BAT motif ( B locks A ddition of T elomeres) previously known to limit telomere elongation and Tel1 activity is also sufficient to block NHEJ and 5’ end resection. The BAT motif inhibits the ability of the Mre11-Rad50-Xrs2 complex (MRX) to capture DNA ends. It acts through a direct contact with Rad50 ATP-binding Head domains. Through genetic approaches guided by structural predictions, we identify residues at the surface of Rad50 that are essential for the interaction with Rif2 and its inhibition. Finally, a docking model predicts how BAT binding could specifically destabilise the DNA-bound state of the MRX complex. From these results, we propose that when an MRX complex approaches a telomere, the Rif2 BAT motif binds MRX Head in its ATP-bound resting state. This antagonises MRX transition to its DNA-bound state, and favours a rapid return to the ATP-bound state. Unable to stably capture the telomere end, the MRX complex cannot proceed with the subsequent steps of NHEJ, Tel1-activation and 5’ resection.

Domains: Life Sciences [q-bio]

Florian Roisné-Hamelin, Sabrina Pobiega, Kévin Jézéquel, Simona Miron, Jordane Dépagne, et al.. Avelumab Versus Docetaxel in Patients With Platinum-Treated Advanced NSCLC: 2-Year Follow-Up From the JAVELIN Lung 200 Phase 3 Trial. Journal of Thoracic Oncology, 2021, 16 (8), pp.1369-1378. ⟨10.1016/j.jtho.2021.03.009⟩. ⟨hal-03627353⟩