Study identifies resistance mechanisms to RAS-targeting molecular glue inhibitors in cancer
This study analyzed paired baseline and end-of-treatment samples from 40 patients treated with the RAS inhibitor daraxonrasib, identifying recurrent alterations in 18 cases that drive resistance to tri-complex inhibitors (TCIs). These molecular glues bind active RAS and recruit cyclophilin A to block oncogenic signaling, but acquired mutations disrupt the synthetic complex formation. The findings reveal distinct resistance mechanisms converging on complex disruption, offering insights for improved drug design and rational combination therapies in RAS mutant cancers.
Key quotes
Tri-complex inhibitors (TCIs) are molecular glues that bind the active, guanosine triphosphate (GTP)-bound state of RAS and recruit cyclophilin A (CYPA) to form a synthetic complex that blocks oncogenic signaling.
Here, we analyzed paired baseline and end-of-treatment samples from 40 patients treated with the RAS inhibitor daraxonrasib and identified recurrent alterations in 18 cases.
Structural and functional analyses revealed that acquired mutations confer resistance through distinct alterations that converge on disrupting synthetic complex formation, exposing strategies for improved drug design and rational combination therapy.
From the article
You might also wanna read
Lab Study Finds Compound Stops 90% of Pancreatic Cancer Cell Migration
Researchers at Florida A&M University have discovered that compounds called polyisoprenylated cysteinyl amide inhibitors can stop 90% of pan
sciencealert.com·6d agoLab Study Finds Compound Stops 90% of Pancreatic Cancer Cell Migration
Researchers at Florida A&M University have discovered that compounds called polyisoprenylated cysteinyl amide inhibitors can stop 90% of pan
sciencealert.com·6d ago
Antibody-ligand motif optimization enables multitarget switchable CAR-T therapy against solid tumors
This article presents a research study on optimizing a multitarget switchable CAR-T (sCAR-T) strategy to overcome antigenic heterogeneity an
A Study of GFH276 Combined With Cetuximab or Chemotherapy in Participants With Solid Tumors and Pancreatic Ductal Adenocarcinoma (PDAC) Harboring RAS Mutation
A hidden weakness in deadly cancers could lead to powerful new treatments
A hidden weakness in deadly cancers could lead to powerful new treatments
A New Strategy for One of the Most Difficult Colorectal Cancer Subtypes – The Babak Lab
Comments
Sign in to join the conversation.
No comments yet. Be the first.