WEE1 confers resistance to KRASG12C inhibitors in non-small cell lung cancer

IF 9.1 1区 医学 Q1 ONCOLOGY
Gaku Yamamoto , Kosuke Tanaka , Ryo Kamata , Hitoshi Saito , Tomoko Yamamori-Morita , Takehiro Nakao , Jie Liu , Shunta Mori , Shigehiro Yagishita , Akinobu Hamada , Yuki Shinno , Tatsuya Yoshida , Hidehito Horinouchi , Yuichiro Ohe , Shun-Ichi Watanabe , Yasushi Yatabe , Hidenori Kitai , Satoshi Konno , Susumu S. Kobayashi , Akihiro Ohashi
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引用次数: 0

Abstract

KRASG12C inhibitors sotorasib and adagrasib have been approved for the treatment of KRASG12C-mutant non-small cell lung cancer (NSCLC). However, the efficacy of single-agent treatments is limited, presumably due to multiple resistance mechanisms. To overcome these therapeutic limitations, combination strategies that potentiate the antitumor efficacy of KRASG12C inhibitors must be developed. Through unbiased high-throughput screening of 1395 kinase inhibitors, we identified adavosertib, a WEE1 inhibitor, as a promising combination partner of sotorasib. The combination of sotorasib and adavosertib exhibited synergistic antiproliferative activities both in vitro and in vivo, irrespective of TP53, STK11, and KEAP1 co-mutation profiles. WEE1 inhibition potentiated MCL-1-mediated apoptosis in sotorasib-treated cancer cells. Mechanistically, the combination downregulated MCL-1 protein levels by attenuating de novo translation and enhancing its degradation. WEE1 overexpression conferred resistance against sotorasib via MCL-1 upregulation. Moreover, cells that acquired sotorasib resistance profoundly upregulated both WEE1 and MCL-1 proteins, highlighting WEE1 as a crucial driver of sotorasib resistance. Importantly, WEE1 inhibition re-sensitized resistant cells to sotorasib treatment. The current findings demonstrate that combined inhibition of KRASG12C and WEE1 not only exhibits synergistic antitumor efficacy but also overcomes resistance to KRASG12C inhibitors, thus representing a novel therapeutic strategy for KRASG12C-mutant NSCLC.
WEE1赋予非小细胞肺癌患者对KRASG12C抑制剂的耐药性
KRASG12C抑制剂sotorasib和adagasib已被批准用于KRASG12C突变型非小细胞肺癌(NSCLC)的治疗。然而,单药治疗的效果是有限的,可能是由于多种耐药机制。为了克服这些治疗局限性,必须开发增强KRASG12C抑制剂抗肿瘤功效的联合策略。通过对1395种激酶抑制剂的无偏高通量筛选,我们确定了WEE1抑制剂adavosertib作为sotorasib的有希望的联合伙伴。无论TP53、STK11和KEAP1共突变谱如何,sotorasib和adavosertib联合使用在体外和体内均表现出协同抗增殖活性。在sotorasib处理的癌细胞中,WEE1抑制增强了mcl -1介导的凋亡。从机制上讲,该组合通过减弱从头翻译和增强其降解来下调MCL-1蛋白水平。WEE1过表达通过上调MCL-1介导对sotorasib的抗性。此外,获得sotorasib抗性的细胞深度上调了WEE1和MCL-1蛋白,突出了WEE1是sotorasib抗性的关键驱动因素。重要的是,WEE1抑制使耐药细胞对sotorasib治疗重新敏感。目前的研究结果表明,联合抑制KRASG12C和WEE1不仅具有协同抗肿瘤功效,而且还克服了KRASG12C抑制剂的耐药性,从而代表了KRASG12C突变型NSCLC的一种新的治疗策略。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Cancer letters
Cancer letters 医学-肿瘤学
CiteScore
17.70
自引率
2.10%
发文量
427
审稿时长
15 days
期刊介绍: Cancer Letters is a reputable international journal that serves as a platform for significant and original contributions in cancer research. The journal welcomes both full-length articles and Mini Reviews in the wide-ranging field of basic and translational oncology. Furthermore, it frequently presents Special Issues that shed light on current and topical areas in cancer research. Cancer Letters is highly interested in various fundamental aspects that can cater to a diverse readership. These areas include the molecular genetics and cell biology of cancer, radiation biology, molecular pathology, hormones and cancer, viral oncology, metastasis, and chemoprevention. The journal actively focuses on experimental therapeutics, particularly the advancement of targeted therapies for personalized cancer medicine, such as metronomic chemotherapy. By publishing groundbreaking research and promoting advancements in cancer treatments, Cancer Letters aims to actively contribute to the fight against cancer and the improvement of patient outcomes.
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