Abstract Targeting KRAS is promising in KRAS-mutant cancers. However, primary and acquired resistance to KRAS inhibitors impedes their clinical use. We conducted a Phase IIa clinical trial enrolling 7 patients with resectable PDAC bearing KRASG12D mutations, who received standard neoadjuvant chemotherapy plus KRAS inhibitors. Genomic analyses revealed acquired mutations in KRAS and other cancer-related. Single-cell transcriptomic profiling showed significant differences in cancer-associated fibroblast (CAF) populations between responders and non-responders. Kinome CRISPR library screening and FDA-approved compound library screening nominated the JAK-STAT pathway as critical for response to KRAS inhibition. Cell lines resistant to KRAS inhibitors have activated JAK-STAT pathway. In vitro and in vivo, STAT3 inhibition synergized with KRAS inhibition, altered cytokine secretion by cancer cells, and modulated CAF status. These findings demonstrate that activation of the JAK-STAT pathway is a common mechanism of resistance to KRAS inhibitors in diverse KRAS-mutant cancers and suggest that dual targeting of KRAS and STAT3 may enhance therapeutic efficacy. Citation Format: Yi Zhao, Yizhi Cao, Yu Bao, Baiyong Shen. Targeting the JAK-STAT pathway sensitizes KRAS-mutant cancer to KRAS inhibitors abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts) ; 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86 (7 Suppl): Abstract nr 6771.
Zhao et al. (Fri,) studied this question.