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KRAS secondary mutations that confer acquired resistance to KRAS G12C inhibitors, sotorasib and adagrasib, and overcoming strategies: insights from the in vitro experiments

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 shown promising results in metastatic non-small cell lung cancer. However, it is strongly anticipated that acquired resistance will limit their clinical utility. In this study, we developed in vitro models of the KRAS G12C cancer, derived 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 (ENU) 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/S was resistant to both inhibitors. A combination of novel SOS1 inhibitor, BI-3406, and trametinib showed potent activity against this resistance. While G13D, R68M and A59S/T 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. Additionally, switching to BI-3406 plus trametinib might be a useful strategy to overcome acquired resistance due to the secondary Y96D/S mutation.

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