KRAS Secondary Mutations That Confer Acquired Resistance to KRAS G12C Inhibitors, Sotorasib and Adagrasib, and Overcoming Strategies: Insights From In Vitro Experiments

克拉斯 医学 体外 癌症研究 交叉电阻 癌症 突变 生物 遗传学 内科学 基因 结直肠癌 病毒学
作者
T Koga,Kenichi Suda,Toshio Fujino,Shuta Ohara,Akira Hamada,Masaya Nishino,Masato Chiba,Masaki Shimoji,Toshiki Takemoto,Takeo Arita,Michael Gmachl,Marco H. Hofmann,Junichi Soh,Tetsuya Mitsudomi
出处
期刊:Journal of Thoracic Oncology [Elsevier]
卷期号:16 (8): 1321-1332 被引量:149
标识
DOI:10.1016/j.jtho.2021.04.015
摘要

Abstract

Introduction

KRAS mutations have been recognized as undruggable for many years. Recently, novel KRAS G12C inhibitors, such as sotorasib and adagrasib, are being developed in clinical trials and have revealed promising results in metastatic NSCLC. Nevertheless, it is strongly anticipated that acquired resistance will limit their clinical use. In this study, we developed in vitro models of the KRAS G12C cancer, derived from resistant clones against sotorasib and adagrasib, and searched for secondary KRAS mutations as on-target resistance mechanisms to develop possible strategies to overcome such resistance.

Methods

We chronically exposed Ba/F3 cells transduced with KRASG12C to sotorasib or adagrasib in the presence of N-ethyl-N-nitrosourea and searched for secondary KRAS mutations. Strategies to overcome resistance were also investigated.

Results

We generated 142 Ba/F3 clones resistant to either sotorasib or adagrasib, of which 124 (87%) harbored secondary KRAS mutations. There were 12 different secondary KRAS mutations. Y96D and Y96S were resistant to both inhibitors. A combination of novel SOS1 inhibitor, BI-3406, and trametinib had potent activity against this resistance. Although G13D, R68M, A59S and A59T, which were highly resistant to sotorasib, remained sensitive to adagrasib, Q99L was resistant to adagrasib but sensitive to sotorasib.

Conclusions

We identified many secondary KRAS mutations causing resistance to sotorasib, adagrasib, or both, in vitro. The differential activities of these two inhibitors depending on the secondary mutations suggest sequential use in some cases. In addition, switching to BI-3406 plus trametinib might be a useful strategy to overcome acquired resistance owing to the secondary Y96D and Y96S mutations.
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