Targeting mutant KRAS has been challenging for several reasons. First, the K-Ras protein has a smooth surface with few pockets suitable for drug binding, making it difficult to develop small molecules that directly inhibit its activity. Second, the mutant protein is constitutively active, so simply blocking upstream signals is ineffective. Finally, the downstream signaling pathways activated by mutant KRAS are complex and redundant, meaning that inhibiting one pathway may not be sufficient to stop cancer growth.
