# Peptides That Block RAS-p21 Protein-Induced Cell Transformation
## 5 Assessment of Peptide Therapy for Ras-Induced Tumors  
Table 1 summarizes each of the peptides and small molecules discussed above that have either been proved to be clinically effective or to have significant potential for treating RAS-p21-induced cancers. Included in this table are the effects of each agent on cancer cells and, importantly, on normal or untransformed cells. \begin{table}
\begin{tabular}{c c c c} \hline
**Source of Peptide or** **Small Molecule** & **Amino Acid Sequence or** **Small Molecule** & **Site of Action** & **Effect on Cancer Cells** & **Effect on Normal Cells** \\ \hline RAS-p21,35–47 (PNC-7) 1 & TIEDSYRKQVVID and TIEDSYRKQVVID-Leader 2 & G12V-H-RAS-p21 binding to RAF & Leader form induces phenotypic & Leader form has no effect \\  & & & & on rat BMRPA1 \\  & & & & \\ RAS-p21,96–110 (PNC-2) 1 & YREQIKRVKDSDDVP and YREQIKRVKDSDDVP-Leader 2 & G12V-H-RAS-p21 binding to JNK, SOS & Leader form induces phenotypic & and human \\  & & & & \\ RAS-p21,96–110 (PNC-2) 1 & YREQIKRVKDSDDVP and YREQIKRVKDSDDVP-Leader 2 & G12V-H-RAS-p21 binding to JNK, SOS & Leader form induces phenotypic & Leader form has no effect \\  & & & & on rat BMRPA1 \\  & & & & \\ RAS-p21,96–110 (PNC-2) 1 & YREQIKRVKDSDDVP and YREQIKRVKDSDDVP-Leader 2 & G12V-H-RAS-p21 binding to JNK, SOS & Leader form induces phenotypic & Leader form has no effect \\  & & & & on rat BMRPA1 \\  & & & & \\ RAS-p21,96–110 (PNC-2) 1 & YREQIKRVKDSDDVP and YREQIKRVKDSDDVP-Leader 2 & G12V-H-RAS-p21 binding to JNK, SOS & Leader form induces phenotypic & Leader form has no effect \\  & & & & on rat BMRPA1 \\  & & & & \\ RAS-p21,96–110 (PNC-2) 1 & YREQIKRVKDSDDVP and YREQIKRVKDSDDVP-Leader 2 & G12V-H-RAS-p21 binding to JNK, SOS & Leader form induces phenotypic & Leader form has no effect \\  & & & & on rat BMRPA1 \\  & & & & pancreatic acinar cells \\  & & & & and human \\  & & & & \\  & & & & \\  & & & & \\  & & & & \\  & & & & \\ \end{tabular}
\end{table} 
Table 1: Peptides and Small Molecules that Block Oncogenic RAS-P21. \begin{table}
\begin{tabular}{c c c c c} \hline \hline
**Source of Peptide or** & **Amino Acid Sequence or** & **Site of Action** & **Effect on Cancer Cells** & **Effect on Normal Cells** \\
Considering that RAS-p21 has been considered to be \"undruggable,\" there have been noticeable advances in therapeutic modalities for ras-induced tumors. Careful studies of the X-ray crystal structures of different oncogenic forms of RAS-p21 bound to GDP or GTP have revealed grooves that allow for the insertion of specific (cyclic) peptides or polyaromatic small molecules such as KD2, AMG510 and MRTX 849 (and 1139) that selectively block signal transduction by specific mutations in RAS-p21. AMG510 (Sotorasib) and MRTX 849 (Anagrasib) have already been FDA-approved for the treatment of ras-induced tumors, provided that they have the specific G12C mutation and promise to be effective agents in oncological treatment. If KD2 and similar cyclic peptides can be modified to cross cell membranes, these may prove likewise to be effective agents against G12D-RAS-p21-induced cancers. In this regard, MRTX1139 is another promising drug that blocks G12D-K-RAS-p21 by freezing it in the inactive GDP state. Thus, both KD2 and MRTX1133 target G12D mutant RAS-p21, the former in an inactive GTP-bound state, the latter in the inactive GDP-bound state, suggesting that these agents can act synergistically. It should be noted that the two FDA-approved drugs, AMG510 and MRTX849, target exclusively G12C-K-RAS-p21. This oncogenic form occurs most frequently in adenocarcinomas of the lung. About 40 percent of ras-induced tumors of this type harbor this mutation [39]. Its occurrence is much less common in all other solid tissue tumors [39]. On the other hand, as a percentage of all ras-induced tumors, G12D-K-RAS-p21 occurs in about 25 percent of lung adenocarcinomas, 37 percent in colon cancers and 50 percent in pancreatic cancers [39]. Thus, targeting this mutant RAS-p21 form is of major concern.