Article ; Online: KRAS Secondary Mutations That Confer Acquired Resistance to KRAS G12C Inhibitors, Sotorasib and Adagrasib, and Overcoming Strategies: Insights From In Vitro Experiments.
2021 Volume 16, Issue 8, Page(s) 1321–1332
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. ... ...
| 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 KRAS 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. |
|---|---|
| MeSH term(s) | Carcinoma, Non-Small-Cell Lung ; Humans ; Lung Neoplasms/drug therapy ; Lung Neoplasms/genetics ; Mutation ; Piperazines ; Proto-Oncogene Proteins p21(ras)/genetics ; Pyridines ; Pyrimidines |
| Chemical Substances | KRAS protein, human ; Piperazines ; Pyridines ; Pyrimidines ; sotorasib (2B2VM6UC8G) ; Proto-Oncogene Proteins p21(ras) (EC 3.6.5.2) |
| Language | English |
| Publishing date | 2021-05-07 |
| Publishing country | United States |
| Document type | Journal Article ; Research Support, Non-U.S. Gov't |
| ZDB-ID | 2432037-7 |
| ISSN | 1556-1380 ; 1556-0864 |
| ISSN (online) | 1556-1380 |
| ISSN | 1556-0864 |
| DOI | 10.1016/j.jtho.2021.04.015 |
| Database | MEDical Literature Analysis and Retrieval System OnLINE |
More links
Kategorien
In stock of ZB MED Cologne/Königswinter
| Zs.A 6664: Show issues | Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 2021: Bestellungen von Artikeln über das Online-Bestellformular ab Jg. 2022: Lesesaal (EG) |
|||
| Zs.MO 652: Show issues |
Order via subito
This service is chargeable due to the Delivery terms set by subito. Orders including an article and supplementary material will be classified as separate orders. In these cases, fees will be demanded for each order.