Targeting IRE1 in KRASi-resistant tumors; plus AZ’s Cas9 variant and more

A Science study by Baylor College of Medicine researchers suggests the endoplasmic reticulum stress sensor IRE1 plays a role in resistance of cancers to KRAS inhibition. Inactivation of mutant KRAS down-regulated the IRE1 branch of the unfolded protein response in primary cells from a KRAS G12D-driven pancreatic ductal adenocarcinoma mouse model, and the pathway was reactivated in acquired KRAS inhibitor-resistant cells. Suppression of IRE1 using ORIN1001 from  Shanghai Fosun Pharmaceutical Group Co. Ltd. (Shanghai:600196; HKEX:2196) was effective in enhancing the response of KRAS G12C-driven tumors to Lumakras sotorasib from  Amgen Inc. (NASDAQ:AMGN) in mice.

ORIN1001 is in a Phase I/II study to treat advanced solid tumors and metastatic breast cancer...