In our cell-based RAS-GTP assay we could indeed confirm that the inhibitory effect of sotorasib is not compromised by the H95 mutation in comparison to KRAS(G12C), while the inhibition by adagrasib is nearly abolished (Figure , 4C, and Table ). Cell viability results with either KRAS(G12C/H95Q), HRAS derived mutant, or KRAS(G12C/Y96D) are consistent with the previous findings (Figure ). We observed that the IC50 values for sotorasib were comparable when applied to the double mutant KRAS(G12C/H95Q) and KRAS(G12C), while the effect of the inhibitor on KRAS(G12C/Y96D) was negligible. Agadrasib, on the other hand, followed the non-RAS driven decrease in cell viability, and did not show a specific response in cell viability for cells expressing either KRAS(G12C/H95Q) or KRAS(G12C/Y96D) (Figure , S5B, and Table ). To provide more insights into the role of the secondary mutation Y96D and its negative impact on SII-P inhibitor binding, we conducted MD simulations of the KRAS mutants G12C and G12C/Y96D with non-covalently bound sotorasib in the SII-P. These simulations provide insight into the stability of the inhibitor in the binding site before the covalent reaction takes place with C12. Similarly, as observed in KRAS(WT) simulations, Tyr96 frequently interacts with sotorasib in the context of the G12C mutation, including - and hydrophobic interactions (Figure and S21). These key-interactions are abolished by the Y96D mutation, which consequently leads to instability of sotorasib in the binding site (Figure , S21 and S22). In fact, a complete dissociation of sotorasib from the switch-II pocket was observed at 2000 ns of the simulation in one of the five simulation replicas (Figure ).