Adavosertib (ADA) is a WEE1 inhibitor that exhibits a synthetic lethal effect on p53-mutated gallbladder cancer (GBC). However, drug resistance due to DNA damage response compensation pathways and high toxicity limits further applications. Herein, estrone-targeted ADA-encapsulated metal–organic frameworks (ADA@MOF-EPL) for GBC synthetic lethal treatment by inducing conditional factors are developed. The high expression of estrogen receptors in GBC enables ADA@MOF-EPL to quickly enter and accumulate near the cell nucleus through estrone-mediated endocytosis and release ADA to inhibit WEE1 upon entering the acidic tumor microenvironment. Ultrasound irradiation induces ADA@MOF-EPL to generate reactive oxygen species (ROS), which leads to a further increase in DNA damage, resulting in a higher sensitivity of p53-mutated cancer cells to WEE1 inhibitor and promoting cell death via conditional synthetic lethality. The conditional factor induced by ADA@MOF-EPL further enhances the antitumor efficacy while significantly reducing systemic toxicity. Moreover, ADA@MOF-EPL demonstrates similar antitumor abilities in other p53-mutated solid tumors, revealing its potential as a broad-spectrum antitumor drug.
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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