RNK07421 / Ranok Therap - LARVOL DELTA

Chaperone directed heterobifunctional molecules circumvent KRASG12C inhibitor resistance. (PubMed, Cancer Lett) - "Transcriptomic profiling and functional assays on acquired resistant models to adagrasib identified an enrichment of HSP90 client proteins in resistant phenotypes, suggesting a therapeutic vulnerability. In vivo, RNK07421 significantly reduced tumor burden in xenograft models, outperforming both monotherapies and combination therapies. These findings highlight dual KRASG12C and HSP90 inhibition as a promising strategy to overcome resistance in KRASG12C-driven cancers."

Journal • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • CDC37 • HSP90AA1 • KRAS

Overcoming KRAS G12C inhibitor resistance with a chaperone-mediated protein degrader (CHAMP) (AACR 2023) - "While KRAS has been undruggable, covalent KRAS G12C inhibitors, sotorasib and adagrasib, that bind preferentially to GDP-bound KRAS and prevent exchange for GTP and interaction with downstream effectors, have been approved for use in NSCLC. Furthermore, in vivo treatment with RNK07421 demonstrated dramatic tumor growth inhibition as compared to adagrasib treatment alone. Together, these observations indicate that the novel mechanisms of action of RNK07421 may provide several advantages over G12C inhibitors and possibly other targeted protein degradation agents to effectively treat KRAS G12C-dependent NSCLC."

Late-breaking abstract • Colorectal Cancer • Gastrointestinal Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Pancreatic Cancer • Solid Tumor • HRAS • HSP90AA1 • KRAS • NRAS