Targeting CALR with a small molecule for the treatment of gastric cancer

Purpose Gastric cancer (GC) ranks as the fifth most prevalent malignancy globally, with substantial geographical disparities in incidence rates. The identification of novel pathogenic drivers and their pharmacological inhibitors is therefore critical for advancing precision therapeutics in GC. Based on our prior studies, this paper elucidates the role of Calreticulin (CALR) in regulating gastric cancer cell proliferation and identifies candidate targeted therapeutics. Methods We characterized the regulatory role of CALR in gastric cancer cell proliferation and developed yxx1121, a first-in-class small-molecule inhibitor targeting CALR protein stability. Furthermore, we elucidated the mechanistic basis of CALR-mediated oncogenic regulation in gastric carcinogenesis. Results CALR regulates GC cell proliferation both in vitro and in vivo. Knockdown of CALR significantly promoted GC cell apoptosis, while CALR overexpression markedly suppressed it. CALR inhibition induced G1 phase arrest in GC cells, blocked S phase progression, promoted apoptosis, and inhibited proliferation. Mechanistically, CALR likely modulates GC cell proliferation by regulating the expression and phosphorylation levels of CASP9, c-Myc, p-EGFR, p-STAT3, p-PI3K, and p-AKT. The identified small-molecule inhibitor yxx1121 potently suppressed GC cell proliferation. Conclusion We demonstrate CALR's essential mitotic control in GC models, mechanistically linking its regulation of both apoptotic (CASP9/c-Myc) and oncogenic (EGFR/STAT3/PI3K/AKT) pathways. The first-in-class CALR destabilizer yxx1121 effectively inhibits GC proliferation, positioning it as a promising therapeutic for CALR-dependent gastric cancers.