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September 10, 2025Open Access

WEE1 inhibitor exerts synergistic effect with KRAS G12C inhibitor via MYBL2-RRM2 axis in KRASG12C-mutant lung cancer

Key Points

WEE1 inhibitor enhances the effects of KRAS G12C inhibitors in lung cancer, highlighting a potential treatment strategy.
The combination therapy showed significant efficacy in tumor xenograft models, indicating clinical relevance.
MYBL2-RRM2 axis overexpression can reverse the combined inhibitory effect partially, suggesting a targeted approach.
Combination treatments with clinically available WEE1 inhibitors may offer new hope for patients with KRAS G12C mutations.

Abstract

Abstract The clinical effect of KRAS G12C inhibitors (G12Ci) as monotherapy is poor, prompting the development of combination treatment strategies. Here, we demonstrate that the WEE1 kinase inhibitor (WEE1i), Adavosertib, can sensitize the effect of G12Ci through the MYBL2-RRM2 axis, which is associated with poor prognosis in lung cancer. Overexpressing the MYBL2-RRM2 axis or supplementing the products of the RRM2 enzyme, dNTPs/dNs, can partially reverse this synergistic inhibitory effect. We also observed marked effects of the combination therapy in tumor xenografts models. Collectively, these results uncover the WEE1 kinase inhibitors, some of which are available clinically, as effective enhancers for G12Ci therapy.

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