Kobayashi Keigo, Terai Hideki, Yasuda Hiroyuki, Hamamoto Junko, Hayashi Yuichiro, Takeuchi Osamu, Mitsuishi Yoichiro, Masuzawa Keita, Manabe Tadashi, Ikemura Shinnosuke, Kawada Ichiro, Suzuki Yukio, Soejima Kenzo, Fukunaga Koichi
Division of Pulmonary Medicine, Department of Medicine, Keio University, School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan.
Division of Pulmonary Medicine, Department of Medicine, Keio University, School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan; Clinical and Translational Research Center, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan; Division of Bioreguratory Medicine, Kitasato University School of Pharmacy, 5-9-1, Shirokane, Minato-ku, Tokyo, 108-8641, Japan.
Biochem Biophys Res Commun. 2021 Jan 1;534:1-7. doi: 10.1016/j.bbrc.2020.11.110. Epub 2020 Dec 8.
The development of molecular targeted therapy has improved clinical outcomes in patients with life-threatening advanced lung cancers with driver oncogenes. However, selective treatment for KRAS-mutant lung cancer remains underdeveloped. We have successfully characterised specific molecular and pathological features of KRAS-mutant lung cancer utilising newly developed cell line models that can elucidate the differences in driver oncogenes among tissues with identical genetic backgrounds. Among these KRAS-mutation-associated specific features, we focused on the IGF2-IGF1R pathway, which has been implicated in the drug resistance mechanisms to AMG 510, a recently developed selective inhibitor of KRAS G12C lung cancer. Experimental data derived from our cell line model can be used as a tool for clinical treatment strategy development through understanding of the biology of lung cancer. The model developed in this paper may help understand the mechanism of anticancer drug resistance in KRAS-mutated lung cancer and help develop new targeted therapies to treat patients with this disease.
分子靶向治疗的发展改善了患有具有驱动癌基因的危及生命的晚期肺癌患者的临床结局。然而，针对KRAS突变型肺癌的选择性治疗仍未充分发展。我们利用新开发的细胞系模型成功地描绘了KRAS突变型肺癌的特定分子和病理特征，该模型可以阐明具有相同遗传背景的组织之间驱动癌基因的差异。在这些与KRAS突变相关的特定特征中，我们重点关注了IGF2-IGF1R通路，该通路与AMG 510（一种最近开发的KRAS G12C肺癌选择性抑制剂）的耐药机制有关。通过我们的细胞系模型获得的实验数据可作为通过了解肺癌生物学来制定临床治疗策略的工具。本文开发的模型可能有助于理解KRAS突变型肺癌的抗癌耐药机制，并有助于开发新的靶向疗法来治疗这种疾病的患者。
