KRAS Y96D

We demonstrated a synergistic combination between ADGN-121/Abraxane in pancreatic carcinoma and between ADGN-122/Capecitabine in colon Adenocarcinoma. We showed, that ADGN-123 containing gRNAG12C can effectively reduce the proliferation and inhibit ERK phosphorylation of sotorasib/adagrasib acquired resistance cells harboring KRASG12C/R68M and KRASG12C/Y96D mutations...ConclusionOur study provides a proof-of-concept that ADGN can be applied to target driver mutations of cancers in vivo and permanently disrupt the oncogenic alleles, leading to major tumor regression. ADGN-123 constitutes an alternative strategy to overcome resistance associated to inhibitors of KRASG12C.

Specific KRAS inhibitors, such as sotorasib and adagrasib, have been designed to bind to the protein's mutant structure and block KRAS in its GDP-bound inactive state. Acquired resistance to KRAS inhibitors include novel KRAS mutations such as Y96D/C and other RAS-MAPK effector protein mutations. This review focuses on the intrinsic and acquired mechanisms of resistance to KRAS inhibitors in KRAS mutant non-small cell lung cancer and the potential clinical strategies to overcome or prevent it.