Walid Kamoun, Vice President and Global Head of Reasearch and Development Oncology at Servier, shared on LinkedIn:
“Very important paper for the field. As RAS-inhibitors transform the landscape, understanding acquired resistence will become critical to developing next generation therapies.
Aronchik et al. sequenced paired pretreatment and end-of-treatment ctDNA from 44 patients in the phase 1/2 trial of daraxonrasib. Treatment-emergent alterations in the RAS signaling pathway appeared in most patients.
No acquired secondary KRAS mutations were observed. That is the point of contrast with mutant-selective KRAS G12C(OFF) inhibitors, where on-target secondary mutations dominate the resistance profile.
The authors then reproduced or mechanistically established the same mechanisms in human and murine preclinical models of PDAC, including mutant KRAS and MYC amplification and RTK upregulation.
Thanks to Aronchik et al. for this seminal contribution to the field.”
Title: Acquired resistance to the RAS(ON) multi-selective inhibitor daraxonrasib guides rational combination therapy strategies in pancreatic cancer
Authors: Ida Aronchik, Sumit Kar, Yongxian Zhuang, Ethan Ahler, Lick Pui Lai, Vidya Seshadri, Yu Chi Yang, Ashenafi Bulle, Marie Menard, Biswadeep Nayak, Mark P. Labrecque, Julien Dilly, Eejung Kim, Lingyan Jiang, Jason Yano, Urszula N. Wasko, Ciara Helland, Sean Bredeson, Brett Garrick, Yevgeniy Gindin, Brad Sickler, Xing Wei, Kyle Seamon, Jingjing Jiang, Kian-Huat Lim, Matthew Holderfield, Elsa Quintana, Aparna Hegde, Zeena Salman, Alexander Starodub, Alexander Spira, Wungki Park, David S. Hong, Minal Barve, Meredith Pelster, David Sommerhalder, Salman R. Punekar, Ignacio Garrido-Laguna, Brian M. Wolpin, Anirban Maitra, W. Clay Gustafson, Steve Kelsey, Jacqueline A. M. Smith, Kevin K. Lin, Andrew J. Aguirre, Mallika Singh
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