SHP2 Inhibition Reveals Compensatory PI3K-AKT Activation in KRAS-Driven Pancreatic Cancer: Discovery of SDUY104 and Rational Approaches for Combination Therapy.

Pancreatic cancer remains one of the most lethal malignancies with numerous patients harboring KRAS mutations. Herein, we developed a series of furanyl amide-based SHP2 allosteric inhibitors through optimization of our in-house lead compound SDUY038. Among them, SDUY104 exhibited the most potent enzymatic inhibitory activity and significantly impaired the proliferation of KRAS-driven pancreatic cancer cells by inducing cell-cycle arrest and apoptosis. Mechanistic studies revealed that SDUY104 suppressed MAPK signaling while triggering compensatory PI3K-AKT activation. Combining SDUY104 with an ERK inhibitor Ulixertinib produced synergistic antiproliferative activity via enhanced MAPK suppression. Likewise, coadministrating SDUY104 with a PI3K inhibitor BKM-120 improved antiproliferative efficacy by reversing PI3K-AKT feedback activation. In a PANC-1 xenograft model, combination of SDUY104 with BKM-120 exhibited superior antitumor activity compared to either monotherapy. Collectively, this study identifies a potent SHP2 allosteric inhibitor and delineates a critical compensatory signaling mechanism underlying resistance to SHP2-targeted therapy, providing proof-of-concept support for pancreatic cancer treatment.