# Targeting KRAS in PDAC: A New Way to Cure It?
## 5 Drug Resistance Mechanisms of KRAS Inhibitors
\begin{table}
\begin{tabular}{c c c c c} \hline \hline
**ClinicalTrials.Gov Identifier** & **Title** & **Phase** & **Drugs** & **Targets** \\ \hline \multirow{2}{*}{NCT05379946} & Study to Evaluate D-1553 in & & & D-1553 & KRAS\({}^{\text{G}\text{I}\text{C}}\) \\  & Combination With IN10018 in Subjects & \multirow{2}{*}{\(1/2\)} & IN10018 & FAK \\  & With Solid Tumors & & & \\ \hline \multirow{2}{*}{NCT05074810} & Phase \(1/2\) Study of VS-6766 + Sotorasib & \multirow{2}{*}{\(1/2\)} & Sotorasib & KRAS\({}^{\text{G}\text{I}\text{C}}\) \\  & in G12C NSCLC Patients (RAMP203) & & VS-6766 & RAF/MEK \\ \hline \multirow{4}{*}{NCT05054725} & Combination Study of RMC-4630 and & & & \\  & Sotorasib for NSCLC Subjects With & \multirow{2}{*}{\(2\)} & Sotorasib & KRAS\({}^{\text{G}\text{I}\text{C}}\) \\  & KRASGI2C Mutation After Failure of & & & \\  & Prior Standard Therapies & & & \\ \hline \multirow{2}{*}{NCT05313009} & Tarlov and Sotorasib in Patients With & \multirow{2}{*}{\(1/2\)} & Sotorasib & KRAS\({}^{\text{G}\text{I}\text{C}}\) \\  & KRAS GI2C Mutations & & Tarlovotinib & EGFR/HER2/HER3 \\ \hline \multirow{4}{*}{NCT05198934} & Sotorasib and Panitumumab Versus & \multirow{2}{*}{\(3\)} & Sotorasib & KRAS\({}^{\text{G}\text{I}\text{C}}\) \\  & Investigator’s Choice for Participants & & & \\  & With [PERSON] (KRAS) & & Panitumumab & EGFR \\  & p.G12C Mutation (CodeBreak 300) & & & \\ \hline \multirow{4}{*}{NCT04613596} & Phase 2 Trial of MRTK849 Monotherapy & \multirow{2}{*}{\(2\)} & MRTK849 & KRAS\({}^{\text{G}\text{I}\text{C}}\) \\  & and in Combination With & & & \\  & Pembrolizumab for NSCLC With KRAS & \multirow{2}{*}{\(2\)} & Pembrolizumab & PD-1 \\  & G12C Mutation KRSTAL-7 & & & \\ \hline \multirow{2}{*}{NCT04330664} & Adaprasib in Combination With TNO155 & \multirow{2}{*}{\(1/2\)} & MRTK849 & KRAS\({}^{\text{G}\text{I}\text{C}}\) \\  & in Patients With Cancer (KRYSTAL 2) & & TNO155 & SHP2 \\ \hline \multirow{2}{*}{NCT05375994} & Study of VS-6766 + Adaprasib in KRAS & \multirow{2}{*}{\(1/2\)} & MRTK849 & KRAS\({}^{\text{G}\text{I}\text{C}}\) \\  & G12C NSCLC Patients (RAMP204) & & VS-6766 & RAF/MEK \\ \hline \hline \end{tabular}
\end{table} 
Table 1: \(Cont.\)  
Figure 3: Schematic representation of the RAS signaling pathway and relevant targets for combination therapy regimens. T symbol in red: therapeutic targets combined with KRAS G12 inhibitors in clinical trials (Table 1). RTKs: receptor tyrosine kinases; AUKRA: aurora kinase A; FAK: focal adhesion kinase. way for tumor cells to evade KRAS inhibition [99; 100; 101]. However, the relationship between PI3K and tumor cells evading KRAS inhibition still requires further study. Research on the relationship between the MAPK-ERK pathway and drug resistance mechanisms also continues, but previous clinical attempts to target MEK have not yielded encouraging results [102; 103; 104]. The switch-II pocket is located next to the cys12 residue of the KRAS\({}^{\text{G12C}}\) mutant protein, which is also the binding site for a series of KRAS\({}^{\text{G12C}}\) inhibitors represented by sotorasib [50; 105]. If the structure of this pocket is changed, the inhibitors that target it are likely to be ineffective. In a phase 1 study of MRTX849, a 67-year-old patient with metastatic KRAS\({}^{\text{G12C}}\)-mutated NSCLC was found to have tumor shrinkage of approximately 32% after treatment with MRTX849, but the tumor progressed again after four months. A KRAS mutation, KRAS\({}^{\text{Y96D}}\), was detected in this patient [106]. After intermolecular interaction simulations, it was found that the amino acid substitution at the Y96 site broke the hydrogen bond between it and sotorasib and MRTX849, leading to the breakdown of the inhibitor. This unique KRAS secondary alteration may be a common weakness of KRAS\({}^{\text{G12C}}\) inhibitors currently applied in the clinic.