At this year's ASCO Annual Meeting, investigators also presented encouraging early clinical data for several KRASG12D-selective inhibitors, including RNK08594, GFH375, and DN022150, suggesting that this type of drug could play a role in the treatment of several solid tumors, such as pancreatic ductal adenocarcinoma and non-small cell lung cancer.

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.

Further exploration revealed that, while WFS1 is regulated by the MAPK and PI3K/AKT pathways in MRTX1133-sensitive cells, acquired resistance is associated with downregulation of the E3 ubiquitin ligase Smurf1, leading to increased WFS1 protein stability. Overall, these results highlight WFS1 as an adaptive factor and potential therapeutic target in KRASG12D-driven malignancies, offering a novel approach to enhance the efficacy of KRASG12D inhibitors and overcome acquired resistance.

P2, N=180, Recruiting, Verastem, Inc.

P1/2, N=178, Recruiting, Shenzhen Ionova Life Sciences Co., Ltd. | Not yet recruiting --> Recruiting

P1, N=35, Not yet recruiting, Bayer Consumer Care AG

P1/2, N=120, Not yet recruiting, Verastem Inc.

However, DIO promoted recruitment of gMDSC and reductions in cytotoxic T cells within the 2838c3 T-cell inflamed TME, correlating with loss of control of microscopic disease. These findings suggest that DIO reduces the potency of targeted KRASG12D inhibition in T cell-inflamed PDAC.

P2, N=133, Recruiting, Zhejiang University | N=32 --> 133

P1, N=604, Recruiting, Revolution Medicines, Inc. | Trial primary completion date: Apr 2026 --> Dec 2026

P3, N=670, Recruiting, Revolution Medicines, Inc.

P1/2, N=178, Not yet recruiting, Shenzhen Ionova Life Sciences Co., Ltd.