KRAS drug target: from "undruggable" to therapeutic frontier

KRAS Target Background Introduction

KRAS is the most common proto-oncogene in tumors, encoding a protein that serves as a critical molecular switch in cell signaling, primarily regulating cell proliferation, differentiation, and survival. Mutations frequently occur at amino acid positions 12, 13, and 61, with G12C, G12D, and G12V being the most prevalent. These mutations lead to sustained protein activation, driving tumor initiation and progression. KRAS mutations are highly prevalent in pancreatic cancer, colorectal cancer, and non-small cell lung cancer, and are closely associated with poor prognosis and treatment resistance. Due to its unique structure, KRAS was once considered "undruggable." However, with the successful approval of G12C inhibitors and the rapid development of strategies such as pan-KRAS inhibitors and combination therapies, KRAS has become an important target in cancer treatment.

doi: 10.3390/jcm12020709

Key Mutations in the KRAS Gene

• High-frequency sites: Over 90% of mutations occur at amino acid positions 12, 13, and 61.
• Common subtypes: G12C, G12D, G12V (most clinically significant).
• Tumor distribution: Pancreatic cancer (~90%), colorectal cancer (40%-50%), non-small cell lung cancer (25%-30%).

Progress of Selected KRAS Drugs in Development

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