Reversal of KRAS G12D inhibitor resistance by nimotuzumab via MEK/ERK-mediated unfolded protein response in pancreatic cancer

Pancreatic ductal adenocarcinoma (PDAC) is highly aggressive, with KRAS mutations, particularly KRAS G12D, present in the majority of cases. While development of KRAS G12D inhibitors is rapid, acquired resistance remains a major clinical challenge. Therefore, in this study, we aimed to evaluate the efficacy of novel KRAS G12D inhibitor HRS-4642, investigate its potential resistance mechanisms, and overcome resistance through combination therapy. The results demonstrated that although HRS-4642 showed potent and selective anti-tumor activity, acquired resistance has been observed in a clinical trial (NCT06520488). Through integrated analyses in vitro (HRS-4642-resistant cell lines), in vivo (HRS-4642-resistant patient-derived xenograft (PDX)), and in clinical samples (HRS-4642-resistant patients from NCT06520488), we identified reactivation of the unfolded protein response (UPR) via the MEK/ERK pathway as a key resistance mechanism. To overcome this, we performed a comprehensive drug combination screen and found that nimotuzumab synergized strongly with HRS-4642. This combination effectively enhanced efficacy and reversed resistance both in vitro and in vivo (cell-derived xenograft (CDX) and PDX). Mechanistically, while the addition of nimotuzumab was validated both in vitro and in vivo to sustain the suppression of the MEK/ERK/UPR axis, it concurrently exacerbated endoplasmic reticulum stress in vitro, thereby driving profound cellular damage. Our findings not only reveal a clinically relevant resistance mechanism to KRAS G12D inhibition but also provide a rational, effective combined strategy. Ultimately, the combination of HRS-4642 with nimotuzumab offers a promising therapeutic strategy for PDAC patients harboring KRAS G12D mutations, laying a foundation for advancing clinical research in overcoming resistance to KRAS G12D-targeted therapies.