Sotorasib and adagrasib, the first FDA-approved drugs for KRAS, are both inhibitors that occupy the SII-P. However, their specific interactions with the pocket residues result in individual specificity profiles. Unsurprisingly, this leads to previously reported secondary mutations, inducing drug resistance. 44 KRAS(Y96D) was one of the first reported secondary mutations for adagrasib resistance, and the same mutation was found to confer resistance to multiple KRAS(G12C) inhibitors currently in clinical trials. Later, other KRAS alterations outside the "hotspot" area, such as R68 and H95 have been reported. H95 has been identified as an adagrasib-specific resistance mutation, as sotorasib tolerates mutations in this position. We studied both sotorasib and adagrasib binding in relation to these reported secondary mutations causing clinical resistance. Our data obtained both from biochemical and cell-based assays clearly indicate that adagrasib specificity is driven by its strong interaction with H95, while sotorasib depends heavily on its interaction with Y96, which is conserved in all RAS isoforms. MD simulations further support these observations, additionally indicating sotorasib as a pan-RAS(G12C) drug. Building on this observation we could demonstrate covalent engagement of NRAS(G12C) and HRAS(G12C), and efficacy against cell lines expressing these mutants. We thereby show that sotorasib could be potentially useful for patients carrying a NRAS(G12C) or HRAS(G12C) mutation. The findings of our study are thus consistent with those recently reported by Rubinson et al., who identified a patient with NRAS(G12C) colorectal cancer, and the patient was treated with the combination of sotorasib and the anti-EGFR antibody panitumumab. The patient achieved a marked tumor response with reduction in liver metastases, providing a clinical proof-of-concept that sotorasib can be effective in patients with NRAS(G12C) mutated tumors. Finally, our MD simulations suggest that the Y96D mutation may confer resistance to the majority of SII-P binders by reducing pocket availability via minimizing pocket volume through a de novo salt-bridge between D96 and R68. Overall, the results presented here can support the ongoing development of KRAS or pan-RAS drugs beyond G12C. Our results also highlight how a panel of different methods can unravel functionalities and support each other, when inhibitors are studied in vitro.