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Cell Death & Disease · 2025 ·Vol. 16 ·期 1 ·1-18 · IF 9.6

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

Zhou Chao,Liu Yuqing,Liu Hongyu,Lu Jun,Zhang Bo,Zhu Liang,Wang Shuyuan,Lei Huimin,Han Baohui

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.

CAS / MDL: 2376146-48-2

研究领域: 肿瘤学 · 分子生物学 · 药理学 · 癌症研究

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Cell Death Discovery · 2025 ·Vol. 11 ·期 1 ·1-16 · IF 7

Panobinostat potentiates adagrasib-induced cell death by triggering autophagy in human non-small cell lung cancer

Lu Hui,Fu Wenying,Xia Yiqun,Yan Ying,Shu Chongchong,Chen Yinghua,Xu Chenxin,Zheng Peisen,Shen Xin,Cui Ri,Zou Peng,Ni Daoyong

Adagrasib, a KRASG12C inhibitor, recently received accelerated approval from the US FDA for the treatment of patients diagnosed with KRASG12C-mutated non-small cell lung cancer. Although adagrasib has demonstrated excellent clinical efficacy and good safety, the molecular mechanism underlying the antitumor activity of adagrasib remains elusive. Here, we report that adagrasib treatment markedly inhibited the growth of cells harboring the KRASG12C mutation, whereas the non-KRASG12C cell lines H1299 and PC-9 were also sensitive to adagrasib, indicating that adagrasib exerted off-target effects. Mechanism studies indicated that adagrasib treatment reduced the level of NRF2 via upregulating its ubiquitination, and NRF2 overexpression can reverse the adagrasib-induced cell death in H23 and H1299 cells. Furthermore, adagrasib treatment significantly increased the cellular ROS level and thereby activating autophagy and AKT signaling pathways in H23 and H1299 cells. Importantly, combination of adagrasib with panobinostat demonstrated enhanced antitumor activity in vitro and in vivo. Overall, our data elucidate a novel mechanism of adagrasib, which will be critical for the clinical application of adagrasib.

CAS / MDL: 138-14-7 149647-78-9 1185237-51-7 404950-80-7

研究领域: 肿瘤学 · 药理学 · 分子生物学 · 细胞生物学 · 癌症研究

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

Panobinostat potentiates adagrasib-induced cell death by triggering autophagy in human non-small cell lung cancer