基于 KRASG12C 抑制剂的胰腺癌联合疗法：药物筛选的启示

IF 6.6 2区医学 Q1 Biochemistry, Genetics and Molecular Biology

Molecular Oncology Pub Date : 2024-09-10 DOI:10.1002/1878-0261.13725

Constanza Tapia Contreras, Jonas Dominik Falke, Dana‐Magdalena Seifert, Carolin Schneider, Lukas Krauß, Xin Fang, Denise Müller, Engin Demirdizen, Melanie Spitzner, Tiago De Oliveira, Christian Schneeweis, Jochen Gaedcke, Silke Kaulfuß, Kimia Mirzakhani, Bernd Wollnik, Karly Conrads, Tim Beißbarth, Gabriela Salinas, Jonas Hügel, Nils Beyer, Sophia Rheinländer, Ulrich Sax, Matthias Wirth, Lena‐Christin Conradi, Maximilian Reichert, Volker Ellenrieder, Philipp Ströbel, Michael Ghadimi, Marian Grade, Dieter Saur, Elisabeth Hessmann, Günter Schneider

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引用次数: 0

摘要

胰腺导管腺癌（PDAC）的治疗方案有限，因此迫切需要有效的疗法。PDAC的主要驱动因素是突变的KRAS原癌基因KRA，90%的患者都存在这种情况。KRAS 直接抑制剂的出现为治疗带来了希望，尤其是针对 KRASG12C 突变等位基因的抑制剂，在临床试验中取得了令人鼓舞的结果。然而，由于耐药性的产生，有必要探索强效的联合疗法。我们的目标是通过无偏见的药物筛选找出有效的 KRASG12C 抑制剂联合疗法。结果表明，七无之子同源物1（SOS1）抑制剂、酪氨酸蛋白磷酸酶非受体型11（PTPN11）/Src同源区2域含磷酸酶-2（SHP2）抑制剂和广谱多激酶抑制剂具有协同作用。在一个新颖独特的KRASG12C突变患者衍生类器官模型中进行的验证证实了筛选实验中描述的结果。我们的研究结果提出了提高 KRASG12C 抑制剂疗效的策略，为临床试验设计和肿瘤分子诊断提供了指导。

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KRASG12C‐inhibitor‐based combination therapies for pancreatic cancer: insights from drug screening

Pancreatic ductal adenocarcinoma (PDAC) has limited treatment options, emphasizing the urgent need for effective therapies. The predominant driver in PDAC is mutated KRAS proto‐oncogene, KRA, present in 90% of patients. The emergence of direct KRAS inhibitors presents a promising avenue for treatment, particularly those targeting the KRASG12C mutated allele, which show encouraging results in clinical trials. However, the development of resistance necessitates exploring potent combination therapies. Our objective was to identify effective KRASG12C‐inhibitor combination therapies through unbiased drug screening. Results revealed synergistic effects with son of sevenless homolog 1 (SOS1) inhibitors, tyrosine‐protein phosphatase non‐receptor type 11 (PTPN11)/Src homology region 2 domain‐containing phosphatase‐2 (SHP2) inhibitors, and broad‐spectrum multi‐kinase inhibitors. Validation in a novel and unique KRASG12C‐mutated patient‐derived organoid model confirmed the described hits from the screening experiment. Our findings propose strategies to enhance KRASG12C‐inhibitor efficacy, guiding clinical trial design and molecular tumor boards.

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来源期刊

Molecular Oncology Biochemistry, Genetics and Molecular Biology-Molecular Medicine

CiteScore

11.80

自引率

1.50%

发文量

203

审稿时长

10 weeks

期刊介绍： Molecular Oncology highlights new discoveries, approaches, and technical developments, in basic, clinical and discovery-driven translational cancer research. It publishes research articles, reviews (by invitation only), and timely science policy articles. The journal is now fully Open Access with all articles published over the past 10 years freely available.